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Abstract:

The present invention comprises a new class of compounds useful for the
modulation of Beta-secretase enzyme activity and for the treatment of
Beta-secretase mediated diseases, including Alzheimer's disease (AD) and
related conditions. In one embodiment, the compounds have a general
Formula I
##STR00001##
wherein A1, A2, A3, A4, A5, A6, R2,
R7, X, Y and Z of Formula I are defined herein. The invention also
includes use of these compounds in pharmaceutical compositions for
treatment, prophylactic or therapeutic, of disorders and conditions
related to the activity of beta-secretase protein. Such disorders
include, for example, Alzheimer's Disease, cognitive deficits, cognitive
impairment, schizophrenia and other central nervous system conditions
related to and/or caused by the formation and/or deposition of plaque on
the brain. The invention also comprises further embodiments of Formula I,
intermediates and processes useful for the preparation of compounds of
Formula I.

3. The compound of claim 1, or a a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof, wherein A1 is CH, CF or N;
A2 is CH, CF or N; A3 is CH, CF or N; A4 is CH, CF or N;
A5 is CH, CF, CBr or N; A6 is CH, CF or N; X is --CH2--,
--O-- or --S--; Y is --O--, --S-- or --CH2--, provided that (1) when
X is --O-- or --S--, then Y is --CH2--, or (2) when X is --CH2,
then Y is --O-- or --S--; and Z is CH2, CHF, CF2, CH(CH3),
C(CH3)2 or CH(CF3).

6. The compound of claim 1, or a stereoisomer or pharmaceutically
acceptable salt thereof, wherein R2 is halo, haloalkyl, haloalkoxyl,
C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, CN,
--OC1-6alkyl, --SC1-6alkyl, wherein the C1-6-alkyl,
C2-4alkenyl, C2-4alkynyl and C3-8-cycloalkyl are
optionally substituted, independently, with 1-3 substituents of R9;
each of R1, R4, R5 and R8, independently, is H, F,
methyl, CN or OH; each of R3 and R6, independently, is H, F,
Cl, CF3, methyl, CN, OH, OCH3, SCH3 or NHCH3; R7
is a ring selected from the group consisting of phenyl, pyridyl,
pyrimidyl, pyridazinyl, pyrazinyl, triazinyl and thienyl, said ring
optionally substituted, independently, with 1-3 substituents of R9;
X is --CH2--, --O-- or --S--; Y is --O--, --S-- or --CH2--,
provided that (1) when X is --O-- or --S--, then Y is --CH2--, or
(2) when X is --CH2, then Y is --O-- or --S--; and Z is CH.sub.2.

12. A pharmaceutical composition comprising a compound according to claim
1 and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising a compound according to claim
11 and a pharmaceutically acceptable excipient.

14. A method of reducing the levels of beta amyloid peptide in the
cerebral spinal fluid of a subject, the method comprising administering
to the subject an effective dosage amount of a compound according to
claim 1.

15. A method of treating Alzheimer's disease, cognitive impairment or a
combination thereof in a subject, the method comprising administering to
the subject an effective dosage amount of a compound of claim 1.

16. A method of treating Alzheimer's disease, cognitive impairment or a
combination thereof in a subject, the method comprising administering to
the subject an effective dosage amount of a pharmaceutical composition of
claim 12.

18. A method of slowing the formation of plaque on the brain of a
subject, the method comprising administering to the subject an effective
dosage amount of a compound according to claim 11.

19. A method of slowing the formation of plaque on the brain of a
subject, the method comprising administering to the subject an effective
dosage amount of a pharmaceutical composition according to claim 13.

20. A process for preparing a compound of claim 1, the process comprising
the step of reacting a compound 20 ##STR00147## wherein A1,
A2, A3, A4, A5, A6, R2, X, Y and Z of
Formula I are as defined in claim 1, with a compound having the structure
##STR00148## or R7--B(OH)2, wherein R7 is as defined in
claim 1 to prepare the compound of claim 1.

Description:

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application
No. 61/314,024, filed Mar. 15, 2010, which specification is hereby
incorporated here in by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates generally to pharmaceutically active
compounds, pharmaceutical compositions and methods of use thereof, to
treat Beta-Secretase mediated diseases and conditions, including, without
limitation, Alzheimer's disease, plaque formation on the brain and
related disorders.

BACKGROUND OF THE INVENTION

[0003] Alzheimer's disease (AD) affects greater than 12 million aging
people worldwide. AD accounts for the majority of dementia clinically
diagnosed after the age of 60. AD is generally characterized by the
progressive decline of memory, reasoning, judgement and orientation. As
the disease progresses, motor, sensory, and vocal abilities are affected
until there is global impairment of multiple cognitive functions. The
loss of cognitive function occurs gradually, typically leading to a
diminished cognition of self, family and friends. Patients with severe
cognitive impairment and/or diagnosed as end-stage AD are generally
bedridden, incontinent, and dependent on custodial care. The AD patient
eventually dies in about nine to ten years, on average, after initial
diagnosis. Due to the incapacitating, generally humiliating and
ultimately fatal effects of AD, there is a need to effectively treat AD
upon diagnosis.

[0004] AD is characterized by two major physiological changes in the
brain. The first change, beta amyloid plaque formation, supports the
"amyloid cascade hypothesis" which conveys the thought that AD is caused
by the formation of characteristic beta amyloid peptide (A-beta), or
A-beta fragments thereof, deposits in the brain (commonly referred to as
beta amyloid "plaques" or "plaque deposits") and in cerebral blood
vessels (beta amyloid angiopathy). A wealth of evidence suggests that
beta-amyloid and accompanying amyloid plaque formation is central to the
pathophysiology of AD and is likely to play an early role in this
intractable neurodegenerative disorder. The second change in AD is the
formation of intraneuronal tangles, consisting of an aggregate form of
the protein tau. Besides being found in patients with AD, intraneuronal
tangles are also found in other dementia-inducing disorders. Joachim et
al., Alz. Dis. Assoc. Dis., 6:7-34 (1992).

[0005] Several lines of evidence indicate that progressive cerebral
deposition of A-beta plays a seminal role in the pathogenisis of AD and
can precede cognitive symptoms by years or even decades. Selkoe, Neuron,
6:487 (1991). Release of A-beta from neuronal cells grown in culture and
the presence of A-beta in cerebrospinal fluid (CSF) of both normal
individuals and AD patients has been demonstrated. Seubert et al.,
Nature, 359:325-327 (1992). Autopsies of AD patients have revealed large
numbers of lesions comprising these 2 factors in areas of the human brain
believed to be important for memory and cognition.

[0006] Smaller numbers of these lesions in a more restricted anatomical
distribution are found in the brains of most aged humans who do not have
clinical AD. Amyloid containing plaques and vascular amyloid angiopathy
were also found in the brains of individuals with Down's Syndrome,
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type
(HCHWA-D), and other neurodegenerative disorders.

[0007] It has been hypothesized that A-beta formation is a causative
precursor or factor in the development of AD. More specifically,
deposition of A-beta in areas of the brain responsible for cognitive
factors is believed to be a major factor in the development of AD. Beta
amyloid plaques are primarily composed of amyloid beta peptide (A-beta
peptide). A-beta peptide is derived from the proteolytic cleavage of a
large transmembrane amyloid precursor protein (APP), and is a peptide
ranging in about 39-42 amino acid residues. A-beta 42 (42 amino acids
long) is thought to be the major component of these plaque deposits in
the brains of Alzheimer's Disease patients. Citron, Trends in
Pharmacological Sciences, 25(2):92-97 (2004).

[0008] Similar plaques appear in some variants of Lewy body dementia and
in inclusion body myositis, a muscle disease. Aβ also forms
aggregates coating cerebral blood vessels in cerebral amyloid angiopathy.
These plaques are composed of a tangle of regularly ordered fibrillar
aggregates called amyloid fibers, a protein fold shared by other peptides
such as prions associated with protein misfolding diseases. Research on
laboratory rats suggest that the two-molecule, soluble form of the
peptide is a causative agent in the development of Alzheimer's and that
the two-molecule form is the smallest synaptotoxic species of soluble
amyloid beta oligomer. Shankar, G. M., Nature Medicine (Jun. 22, 2008)
online doi 10:1038 nm 1782.

[0009] Several aspartyl proteases are thought to be involved in the
processing or cleavage of APP, resulting in the formation of A-beta
peptide. Beta secretase (BACE, also commonly referred to as memapsin) is
thought to first cleave APP to generate two fragments: (1) a first
N-terminus fragment (beta APP) and (2) a second C-99 fragment, which is
subsequently cleaved by gamma secretase to generate the A-beta peptide.
APP has also found to be cleaved by alpha-secretase to produce
alpha-sAPP, a secreted form of APP that does not result in beta-amyloid
plaque formation. This alternate pathway precludes the formation of
A-beta peptide. A description of the proteolytic processing fragments of
APP is found, for example, in U.S. Pat. Nos. 5,441,870, 5,712,130 and
5,942,400.

[0010] BACE is an aspartyl protease enzyme comprising 501 amino acids and
responsible for processing APP at the beta-secretase specific cleavage
site. BACE is present in two forms, BACE 1 and BACE 2, designated as such
depending upon the specific cleavage site of APP. Beta secretase is
described in Sinha et al., Nature, 402:537-554 (1999) (p510) and PCT
application WO 2000/17369. It has been proposed that A-beta peptide
accumulates as a result of APP processing by BACE. Moreover, in vivo
processing of APP at the beta secretase cleavage site is thought to be a
rate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis.
Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity is
desirable for the treatment of AD.

[0011] Studies have shown that the inhibition of BACE may be linked to the
treatment of AD. The BACE enzyme is essential for the generation of
beta-amyloid or A-beta. BACE knockout mice do not produce beta-amyloid
and are free from Alzheimer's associated pathologies including neuronal
loss and certain memory deficits. Cole, S. L., Vasser, R., Molecular
Degeneration 2:22, 2007. When crossed with transgenic mice that over
express APP, the progeny of BACE deficient mice show reduced amounts of
A-beta in brain extracts as compares with control animals (Luo et al.,
Nature Neuroscience, 4:231-232 (2001)). The fact that BACE initiates the
formation of beta-amyloid, and the observation that BACE levels are
elevated in this disease provide direct and compelling reasons to develop
therapies directed at BACE inhibition thus reducing beta-amyloid and its
associated toxicities. To this end, inhibition of beta secretase activity
and a corresponding reduction of A-beta in the brain should provide a
therapeutic method for treating AD and other beta amyloid or plaque
related disorders.

[0013] The present invention provides a new class of compounds useful for
the modulation of beta secretase activity. To that end, the compounds of
the invention are useful for the regulation or reduction of the formation
of A-beta peptide and, consequently, the regulation and/or reduction of
beta amyloid plaque formation on the brain. Accordingly, the compounds
are useful for the treatment of Alzheimer's disease and other beta
secretase and/or plaque mediated disorders. For example, the compounds
are useful for the prophylaxis and/or treatment, acute and/or chronic, of
AD and other diseases or conditions involving the deposition or
accumulation of beta amyloid peptide, and formation of plaque, on the
brain.

[0014] The compounds provided by the invention, including stereoisomers,
tautomers, solvates, pharmaceutically acceptable salts, derivatives or
prodrugs thereof, are generally defined by Formula I

##STR00002##

wherein A1, A2, A3, A4, A5, A6, R2,
R7, X, Y and Z of Formula I are described below. The invention also
provides procedures for making compounds of sub-Formulas thereof, as well
as intermediates useful in such procedures.

[0015] The invention further provides pharmaceutical compositions, which
comprise one or more compounds of the invention, methods for the
treatment of beta secretase mediated diseases, such as AD, using the
compounds and compositions of the invention. For example, and in one
embodiment, the invention provides a pharmaceutical composition
comprising an effective dosage amount of a compound of Formula I in
association with at least one pharmaceutically acceptable excipient.

[0016] The foregoing merely summarizes certain aspects of the invention
and is not intended, nor should it be construed, as limiting the
invention in any way. All patents and other publications recited herein
are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

[0017] In one embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable salts
thereof, are generally defined by the compound of Formula I:

[0088] R7 is a ring selected from the group consisting of phenyl,
pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl and thienyl, said
ring optionally substituted, independently, with 1-3 substituents of
R9; and

[0089] X is --O-- or --S--.

[0090] In another embodiment of the present invention, the compounds, and
solvates, tautomers, stereoisomers and pharmaceutically acceptable salts
thereof, are defined by Formula II-B

##STR00007##

wherein A1 is CH or CF;

[0091] A2 is CH or CF;

[0092] A3 is CH, CF or N;

[0093] A4 is CH, CF or N;

[0094] A5 is CH;

[0095] A6 is CH or CF, provided that no more than one of A3 and
A4 is N;

[0114] R7 is a ring selected from the group consisting of phenyl,
pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl and thienyl, said
ring optionally substituted, independently, with 1-3 substituents of
R9; and

[0115] Y is --O-- or --S--.

[0116] In another embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable salts,
are generally defined by Formula I-A-1, wherein

##STR00008##

[0117] each of R1, R5 and R8, independently, is H;

[0118] A1 is CH, CF or N;

[0119] A3 is CH, CF or N;

[0120] A4 is CH, CF or N, provided that no more than one of A1,
A3 and A4 is N;

[0134] Y is --O--, --S-- or --CH2--, provided that (1) when X is
--O-- or --S--, then Y is --CH2--, or (2) when X is --CH2, then
Y is --O-- or --S--.

[0135] In another embodiment of the invention, the compounds, including
stereoisomers, and pharmaceutically acceptable salts, are generally
defined by Formula I-A-1, wherein

[0136] each of R1, R5 and R8, independently, is H;

[0137] A1 is CH;

[0138] A3 is CH, CF or N;

[0139] A4 is CH, CF or N, provided that no more than one of A3
and A4 is N;

[0140] R2 is a ring selected from the group consisting of pyridine,
pyrrolidine, piperidine, phenyl, dihydropyran, and morpholine or R2
is --O--C1-6alkyl, C1-6alkynyl, wherein the ring,
--O--C1-6allyl and C1-6alkynyl are optionally substituted
independently with 1-5 substituents of R9;

[0141] R7 is a a ring selected from the group consisting of pyridine
and phenyl, wherein the ring is optionally substituted independently with
1-3 substituents of R9; each R9 is, independently, F, Cl, Br,
C1-6alkyl, C1-6alkenyl, C1-6alkynyl, --OC1-6alkyl,
CN, CF3, --OCF3 or spiro-oxetanyl;

[0142] X is --CH2--, --O-- or --S--; and

[0143] Y is --O--, --S-- or --CH2--, provided that (1) when X is
--O-- or --S--, then Y is --CH2--, or (2) when X is --CH2, then
Y is --O-- or --S--.

[0144] In another embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable salts,
are generally defined by Formula I-A-2

[0192] In another embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable salts
thereof, are generally defined by the compound of Formula I-B:

[0199] Y is --O--, --S-- or --CH2--, provided that (1) when X is
--O-- or --S--, then Y is --CH2--, or (2) when X is --CH2, then
Y is --O-- or --S--; and

[0200] Z is CH2, CF2 or CH(CH3).

[0201] In another embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable salts
thereof, are generally defined by the compound of Formula I-B, wherein

[0207] Y is --O--, --S-- or --CH2--, provided that (1) when X is
--O-- or --S--, then Y is --CH2--, or (2) when X is --CH2, then
Y is --O-- or --S--; and

[0208] Z is CH2 or CH(CH3).

[0209] In another embodiment of the invention, the compounds, including
stereoisomers, tautomers, solvates, pharmaceutically acceptable salts
thereof, are generally defined by the compound of Formula I-B, wherein

[0210] A4 is CH, CF or N;

[0211] R4 is H or F;

[0212] R2 is a ring selected from the group consisting of pyridine,
pyrrolidine, piperidine, phenyl, dihydropyran and morpholine or R2
is --O--C1-6allyl, C1-6alkynyl, wherein the ring,
--O--C1-6alkyl and C1-6alkynyl are optionally substituted
independently with 1-5 substituents of R9;

[0213] R7 is a a ring selected from the group consisting of pyridine
and phenyl, wherein the ring is optionally substituted independently with
1-3 substituents of R9;

[0216] Y is --O--, --S-- or --CH2--, provided that (1) when X is
--O-- or --S--, then Y is --CH2--, or (2) when X is --CH2, then
Y is --O-- or --S--; and

[0217] Z is CH2 or CH(CH3).

[0218] In another embodiment of the invention, the compounds of the
invention include compounds wherein X is O or S when Y and Z are each
--CH2--, in conjunction with any of the above or below embodiments.

[0219] In another embodiment of the invention, the compounds of the
invention include compounds wherein Y is O or S when X and Z are each
--CH2--, in conjunction with any of the above or below embodiments.

[0220] In another embodiment of the invention, the compounds of the
invention include compounds wherein X is O, and Y and Z are each
CH2, in conjunction with any of the above or below embodiments.

[0221] In another embodiment of the invention, the compounds of the
invention include compounds wherein X is S, and Y and Z are each
CH2, in conjunction with any of the above or below embodiments.

[0222] In another embodiment of the invention, the compounds of the
invention include compounds wherein X and Z are each --CH2-- and Y
is O, in conjunction with any of the above or below embodiments.

[0223] In another embodiment of the invention, the compounds of the
invention include compounds wherein X and Z are each --CH2-- and Y
is S, in conjunction with any of the above or below embodiments.

[0224] In another embodiment of the invention, the compounds of the
invention include compounds wherein Z is CH2, CHF, CF2,
CH(CH3), C(CH3)2 or CH(CF3), in conjunction with any
of the above or below embodiments.

[0225] In another embodiment of the invention, the compounds of the
invention include compounds wherein Z is CH2, CF2 or
C(HCH3), in conjunction with any of the above or below embodiments.

[0226] In another embodiment of the invention, the compounds of the
invention include compounds wherein Z is CH2 or C(CH3), in
conjunction with any of the above or below embodiments.

[0227] In another embodiment of the invention, the compounds of the
invention include compounds wherein Z is CH2, in conjunction with
any of the above or below embodiments.

[0228] The present invention contemplates that the various different
embodiments below of each individual variable A1, A2, A3,
A4, A5, A6, R2, R7, X, Y and Z, as described
below, may be applied "in conjunction with any of the other {above and
below} embodiments" to create various embodiments of general Formulas I
and II, and each sub-formula thereof, described hereinabove, which are
not literally described herein.

[0229] In another embodiment, the invention includes compounds wherein
A1 is CH, CF or N, in conjunction with any of the above or below
embodiments.

[0230] In another embodiment, the invention includes compounds wherein
A1 is CH, in conjunction with any of the above or below embodiments.

[0231] In another embodiment, the invention includes compounds wherein
A1 is CF, in conjunction with any of the above or below embodiments.

[0232] In another embodiment, the invention includes compounds wherein
A1 is N, in conjunction with any of the above or below embodiments.

[0233] In another embodiment, the invention includes compounds wherein
A2 is CH, CF or N, in conjunction with any of the above or below
embodiments.

[0234] In another embodiment, the invention includes compounds wherein
A2 is CH, in conjunction with any of the above or below embodiments.

[0235] In another embodiment, the invention includes compounds wherein
A2 is CF, in conjunction with any of the above or below embodiments.

[0236] In another embodiment, the invention includes compounds wherein
A2 is N, in conjunction with any of the above or below embodiments.

[0237] In another embodiment, the invention includes compounds wherein
A3 is CH, CF or N, in conjunction with any of the above or below
embodiments.

[0238] In another embodiment, the invention includes compounds wherein
A3 is CH, in conjunction with any of the above or below embodiments.

[0239] In another embodiment, the invention includes compounds wherein
A3 is CF, in conjunction with any of the above or below embodiments.

[0240] In another embodiment, the invention includes compounds wherein
A3 is N, in conjunction with any of the above or below embodiments.

[0241] In another embodiment, the invention includes compounds wherein
A4 is CH, CF or N, in conjunction with any of the above or below
embodiments.

[0242] In another embodiment, the invention includes compounds wherein
A4 is CH, in conjunction with any of the above or below embodiments.

[0243] In another embodiment, the invention includes compounds wherein
A4 is CF, in conjunction with any of the above or below embodiments.

[0244] In another embodiment, the invention includes compounds wherein
A4 is N, in conjunction with any of the above or below embodiments.

[0245] In another embodiment, the invention includes compounds wherein
A5 is CH, CR1 wherein R1 is F, Br or

##STR00016##

or A5 is N, in conjunction with any of the above or below
embodiments.

[0246] In another embodiment, the invention includes compounds wherein
A5 is CH, in conjunction with any of the above or below embodiments.

[0247] In another embodiment, the invention includes compounds wherein
A5 is CR1 wherein R1 is F, Br or

##STR00017##

in conjunction with any of the above or below embodiments.

[0248] In another embodiment, the invention includes compounds wherein
A5 is N, in conjunction with any of the above or below embodiments.

[0249] In another embodiment, the invention includes compounds wherein
A6 is CH, CF or N, in conjunction with any of the above or below
embodiments.

[0250] In another embodiment, the invention includes compounds wherein
A6 is CH, in conjunction with any of the above or below embodiments.

[0251] In another embodiment, the invention includes compounds wherein
A6 is CF, in conjunction with any of the above or below embodiments.

[0252] In another embodiment, the invention includes compounds wherein
A6 is N, in conjunction with any of the above or below embodiments.

[0256] In another embodiment, the invention includes compounds wherein
R2 is C2-4alkynyl, OC1-6alkyl, pyridyl, pyrimidyl,
dihydropyranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, wherein
the C2-4alkynyl, OC1-6alkyl, pyridyl, pyrimidyl,
dihydropyranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl are
optionally substituted, independently, with 1-3 substituents of R9,
in conjunction with any of the above or below embodiments.

[0258] wherein the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl,
3-methyl-3-oxetanyl-ethynyl, 3-methyl-3-oxetanyl-methoxyl,
3,3-dimethyl-butyn-1-yl, 3-methyl-3-butyn-1-yl,
2,2-dimethyl-3-cyano-propoxyl, 2-fluoro-2-methyl-propoxyl and ring are
optionally substituted, independently, with 1-3 substituents of R9,
in conjunction with any of the above or below embodiments.

[0259] In another embodiment, the invention includes compounds wherein
R2 is 2-fluoro-4-pyridyl, 2-methyl-4-pyridyl, 5-fluoro-3-pyridyl,
4-pyridyl, 2-fluoro-2-methylpropoxyl, 3-fluoro-pyrrolidin-1-yl,
4,4-difluoro-1-piperidinyl, 3-methyl-3-oxetanyl-ethyn-1-yl,
3,3-dimethyl-butyn-1-yl, 4-methylphenyl, 4-fluorophenyl,
5,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,4-difluorophenyl,
2,2-dimethylpropoxyl, 2,2-dimethyl-2-cyano-propoxyl,
3,3-difluoro-1-pyrrolidinyl or 4-morpholinyl, in conjunction with any of
the above or below embodiments.

[0260] In another embodiment, the invention includes compounds wherein
R2 is a ring selected from the group consisting of pyridine,
pyrrolidine, piperidine, phenyl, dihydropyran and morpholine or R2
is --O--C1-6alkyl, C1-6alkynyl, wherein the ring,
--O--C1-6alkyl and C1-6alkynyl are optionally substituted
independently with 1-5 substituents of R9, in conjunction with any
of the above or below embodiments.

[0262] In another embodiment, the invention includes compounds wherein
R7 is C2-4alkynyl, --OC1-6alkyl, phenyl, pyridyl,
pyrimidyl, pyrazinyl or pyridazinyl, wherein the C2-4alkynyl,
--OC1-6alkyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl are
optionally substituted, independently, with 1-3 substituents of R9,
in conjunction with any of the above or below embodiments.

[0263] In another embodiment, the invention includes compounds wherein
R7 is C2-4alkynyl, --OC1-6alkyl, phenyl, 3-pyridyl,
5-pyrimidyl, pyrazinyl or 2-pyridazinyl, wherein the C2-4alkynyl,
--OC1-6alkyl, 3-pyridyl, 5-pyrimidyl, pyrazinyl and 2-pyridazinyl
are optionally substituted, independently, with 1-3 substituents of
R9, in conjunction with any of the above or below embodiments.

[0264] In another embodiment, the invention includes compounds wherein
R7 is a ring selected from the group consisting of phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,
pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,
tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and
morpholinyl, said ring optionally substituted, independently, with 1-3
substituents of R, in conjunction with any of the above or below
embodiments.

[0265] In another embodiment, the invention includes compounds wherein
R7 is a ring selected from phenyl, 3-pyridyl, 5-pyrimidyl or
2-pyridazinyl, said ring optionally substituted, independently, with 1-5
substituents of R9, in conjunction with any of the above or below
embodiments.

[0266] In another embodiment, the invention includes compounds wherein
R7 is phenyl, 3-pyridyl, 5-pyrimidyl or 2-pyridazinyl, each of which
is optionally substituted with 1-5 substituents of F, Cl, Br, I, CN,
CF3, C2F5, haloalkoxyl, CN, OH, OC1-6-alkyl,
SC1-6 alkyl, oxetanyl or C2-3alkynyl, in conjunction with any
of the above or below embodiments.

[0267] In another embodiment, the invention includes compounds wherein
R7 is 3-pyridyl, 2-fluoro-3-pyridyl, 2,5-difluorophenyl,
3,3-dimethyl-1-butynyl, 3-cyanophenyl, 5-fluoro-3-pyridyl,
3,4-difluorophenyl, in conjunction with any of the above or below
embodiments.

[0268] In another embodiment, the invention includes compounds wherein
R7 is 2-fluoro-3-pyridyl, 3-pyridyl, 5-fluoro-3-pyridyl,
2,5-difluorophenyl or 3-fluorophenyl, in conjunction with any of the
above or below embodiments.

[0269] In another embodiment, the invention includes compounds wherein
R7 is a a ring selected from the group consisting of pyridine and
phenyl, wherein the ring is optionally substituted independently with 1-3
substituents of R9, in conjunction with any of the above or below
embodiments.

[0270] In another embodiment, the invention includes compounds wherein

[0274] R7 is a ring selected from the group consisting of phenyl,
pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl and thienyl, said
ring optionally substituted, independently, with 1-3 substituents of
R9;

[0277] Y is --O--, --S-- or --CH2--, provided that (1) when X is
--O-- or --S--, then Y is --CH2--, or (2) when X is --CH2, then
Y is --O-- or --S--; and

[0278] Z is CH2.

[0279] In another embodiment, the invention includes compounds wherein
each R8, independently, is F, Cl, CF3, OCF3, methyl, CN,
OH, OCH3, SCH3, NHCH3, oxetanyl or C2-3alkynyl, in
conjunction with any of the above or below embodiments.

[0280] In another embodiment, the invention includes compounds wherein
each R9, independently, is F, methyl, CN, OH, spiro-oxetanyl or
C2-3alkynyl, in conjunction with any of the above or below
embodiments.

[0281] In another embodiment, the invention includes compounds wherein
each R9, independently, is F, CF3, CN, CH3, --OCH3,
--SCH3, --NHCH3, spiro-oxetanyl or C2-3alkynyl, in
conjunction with any of the above or below embodiments.

[0282] In another embodiment, the invention includes compounds wherein
each R9 is, independently, F, Cl, Br, C1-6alkyl,
C1-6alkenyl, C1-6alkynyl, --OC1-6alkyl, CN, CF3,
--OCF3 or spiro-oxetanyl, in conjunction with any of the above or
below embodiments.

[0283] In another embodiment, the invention provides the compound of
Formula I, or a pharmaceutically acceptable salt thereof, selected from
list the individual compounds described in Table 1 herein.

[0284] In another embodiment, the invention provides the compound of
Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof,
selected from [0285]
(5S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6'H-spiro[chromeno
[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine; [0286]
(5S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoro-3-pyridinyl)-6'H-spiro[chr-
omeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine;

[0343] All of the possible embodiments described herein for various of the
R groups of the compounds of Formula I may be applied, as appropriate, to
compounds of Formulas II, III and IV and any sub-formulas thereof.

[0344] In another embodiment, the invention provides each of the Examplary
compounds, and stereoisomers, tautomers, solvates, pharmaceutically
acceptable salts, derivatives or prodrugs thereof, and related
intermediates, described herein.

[0345] In another embodiment, the invention provides the exemplified
compounds described herein, and pharmaceutically acceptable salt forms of
each thereof.

DEFINITIONS

[0346] The following definitions should assist in understanding the
invention described herein.

[0347] The term "comprising" is meant to be open ended, i.e., all
encompassing and non-limiting. It may be used herein synonymously with
"having." Comprising is intended to include each and every indicated or
recited component or element(s) while not excluding any other components
or elements.

[0348] The term "C.sub.α-βalkyl", when used either alone or
within other terms such as "haloalkyl" and "alkylamino", embraces linear
or branched radicals having α to β number of carbon atoms
(such as C1-C10; C1-C6; or C1-C4). Unless
otherwise specified, one or more carbon atoms of the "alkyl" radical may
be substituted, such as with a cycloalkyl moiety. Examples of "alkyl"
radicals include methyl, cyclopropylmethyl, cyclobutylmethyl,
cyclopentylmethyl, ethyl, cyclopropylethyl, cyclobutylethyl,
cyclopentylethyl, n-propyl, isopropyl, n-butyl, cyclopropylbutyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.

[0349] The term "C.sub.α-βalkenyl", when used alone or in
combination, embraces linear or branched radicals having at least one
carbon-carbon double bond in a moiety having a number of carbon atoms in
the range from α and β. Included within alkenyl radicals are
"lower alkenyl" radicals having two to about six carbon atoms and, for
example, those radicals having two to about four carbon atoms. Examples
of alkenyl radicals include, without limitation, ethenyl, propenyl,
allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and
"lower alkenyl", embrace radicals having "cis" and "trans" orientations,
or alternatively, "E" and "Z" orientations, as appreciated by those of
ordinary skill in the art.

[0350] The term "C.sub.α-βalkynyl", when used alone or in
combination, denotes linear or branched radicals having at least one
carbon-carbon triple bond in a moiety having a number of carbon atoms in
the range from α and β. Examples of alkynyl radicals include
"lower alkynyl" radicals having two to about six carbon atoms and, for
example, lower alkynyl radicals having two to about four carbon atoms.
Examples of such radicals include, without limitation, ethynyl, propynyl
(propargyl), butynyl, and the like.

[0351] The term "C.sub.α-βalkyl", "C.sub.α-βalkenyl"
and "C.sub.α-βalkynyl", when used with other terms such as
"wherein 1, 2 or 3 carbon atoms of said C.sub.α-βalkyl,
C.sub.α-βalkenyl or C2α-β-alkynyl is
optionally replaced with a heteroatom selected from O, S, S(O),
S(O)2 and N" embraces linear or branched radicals wherein one or
more of the carbon atoms may be replaced with a heteroatom. Examples of
such "alkyl" radicals include --O-methyl, --O-ethyl,
--CH2--O--CH3, --CH2CH2--O--CH3, --NH--CH2,
--CH2CH2--N(CH3)--CH3, --S--(CH2)3CH2,
--CH2CH2--S--CH3 and the like. Accordingly, such radicals
also include radicals encompassed by --OR7 where R7 may be
defined as a C.sub.α-βalkyl. Examples of such "alkenyl"
radicals include --NH--CH2CH═CH2,
--S--CH2CH2CH═CHCH3 and the like. Similar examples
exist for such "alkynyl" radicals, as appreciated by those skilled in the
art.

[0352] The term "C.sub.α-βalkoxyl" when used alone or in
combination, embraces linear or branched oxygen-containing alkyl radicals
each having α to β number of carbon atoms (such as
C1-C10). The terms "alkoxy" and "alkoxyl", when used alone or
in combination, embraces linear or branched oxygen-containing radicals
each having alkyl and substituted alkyl portions of one or more carbon
atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy
and tert-butoxy. Alkoxy radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxyl" radicals or with other substitution. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy
(--OCF3), trifluoroethoxy, fluoroethoxy, fluoropropoxy and
cyclopropylmethoxy.

[0353] The term "aryl", when used alone or in combination, means a
carbocyclic aromatic moiety containing one, two or even three rings
wherein such rings may be attached together in a fused manner. Every ring
of an "aryl" multi-ring system need not be aromatic, and the ring(s)
fused to the aromatic ring may be partially or fully unsaturated and
include one or more heteroatoms selected from nitrogen, oxygen and
sulfur. Thus, the term "aryl" embraces aromatic radicals such as phenyl,
naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl,
indanyl, benzodioxazinyl, and the like. The "aryl" group may be
substituted, such as with 1 to 5 substituents including lower alkyl,
hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and
the like. Phenyl substituted with --O--CH2--O-- or
--O--CH2--CH2--O-- forms an aryl benzodioxolyl substituent.

[0354] The term "carbocyclic", also referred to herein as "cycloalkyl" or,
when used alone or in combination, means a partially or fully saturated
ring moiety containing one ("monocyclic"), two ("bicyclic") or even three
("tricyclic") rings wherein such rings may be attached together in a
fused manner and formed from carbon atoms. The term
"C.sub.α-βcycloalkyl" means cycloalkyl radicals each having
α to β number of carbon atoms. Examples of saturated
carbocyclic radicals include saturated 3 to 6-membered monocyclic groups
such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
Carbocycilc may be substituted as described herein.

[0355] The terms "ring" and "ring system" refer to a ring comprising the
delineated number of atoms, the atoms being carbon or, where indicated, a
heteroatom such as nitrogen, oxygen or sulfur. Where the number of atoms
is not delineated, such as a "monocyclic ring system" or a "bicyclic ring
system", the numbers of atoms are 3-8 for a monocyclic and 6-12 for a
bicyclic ring. The ring itself, as well as any substitutents thereon, may
be attached at any atom that allows a stable compound to be formed. The
term "nonaromatic" ring or ring system refers to the fact that at least
one, but not necessarily all, rings in a bicyclic or tricyclic ring
system is nonaromatic.

[0356] The terms "partially or fully saturated or unsaturated" and
"saturated or partially or fully unsaturated" with respect to each
individual ring, refer to the ring either as fully aromatic (fully
unsaturated), partially aromatic (or partially saturated) or fully
saturated (containing no double or triple bonds therein). If not
specified as such, then it is contemplated that each ring (monocyclic) in
a ring system (if bicyclic or tricyclic) may either be fully aromatic,
partially aromatic or fully saturated, and optionally substituted with up
to 5 substituents. This includes carbocyclics, heterocyclics, aryl and
heteroaryl rings.

[0357] Thus, the term "a 3-8 membered monocyclic or 6-12 membered bicyclic
ring system, said ring system formed of carbon atoms optionally including
1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said
heteroatoms selected from O, N, or S, wherein said ring system is
optionally substituted" refers to a single ring of 3-, 4-, 5-, 6-, 7- or
8-atom membered or a 6-, 7-, 8-, 9-, 10-, 11 or 12-atom membered bicyclic
ring system comprising the delineated number of atoms, the atoms being
carbon or, where indicated, a heteroatom such as nitrogen (N), oxygen (O)
or sulfur (S). Where the number of atoms is not delineated, such as a
"monocyclic ring system" or a "bicyclic ring system", the numbers of
atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The ring or
ring system may contain substitutents thereon, attached at any atom that
allows a stable compound to be formed. A bicyclic ring is intended to
include fused ring systems as well as spiro-fused rings. This phrase
encompasses carbocyclics, heterocyclics, aryl and heteroaryl rings.

[0358] The phrase "a saturated or partially or fully unsaturated" when
referring to a 3-8 membered monocyclic or a 6-12 membered bicyclic ring
system is intended to include both aromatic and non-aromatic rings. The
non-aromatic rings may be partially or fully saturated in nature.

[0359] The term "cycloalkenyl", when used alone or in combination, means a
partially or fully saturated cycloalkyl containing one, two or even three
rings in a structure having at least one carbon-carbon double bond in the
structure. Examples of cycloalkenyl groups include C3-C6 rings,
such as compounds including, without limitation, cyclopropene,
cyclobutene, cyclopentene and cyclohexene. The term also includes
carbocyclic groups having two or more carbon-carbon double bonds such as
"cycloalkyldienyl" compounds. Examples of cycloalkyldienyl groups
include, without limitation, cyclopentadiene and cycloheptadiene.

[0360] The term "halo", when used alone or in combination, means halogens
such as fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.

[0361] The term "haloalkyl", when used alone or in combination, embraces
radicals wherein any one or more of the alkyl carbon atoms is substituted
with halo as defined above. For example, this term includes
monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as a
perhaloalkyl. A monohaloalkyl radical, for example, may have either an
iodo, bromo, chloro or fluoro atom within the radical. Dihalo and
polyhaloalkyl radicals may have two or more of the same halo atoms or a
combination of different halo radicals. Examples of haloalkyl radicals
include fluoromethyl, difluoromethyl, trifluoromethyl (--CF3),
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
"Perfluoroalkyl", as used herein, refers to alkyl radicals having all
hydrogen atoms replaced with fluoro atoms. Examples include
trifluoromethyl and pentafluoroethyl.

[0362] The term "heteroaryl", as used herein, either alone or in
combination, means a fully unsaturated (aromatic) ring moiety formed from
carbon atoms and having one or more heteroatoms selected from nitrogen,
oxygen and sulfur. The ring moiety or ring system may contain one
("monocyclic"), two ("bicyclic") or even three ("tricyclic") rings
wherein such rings are attached together in a fused manner. Every ring of
a "heteroaryl" ring system need not be aromatic, and the ring(s) fused
thereto (to the heteroaromatic ring) may be partially or fully saturated
and optionally include one or more heteroatoms selected from nitrogen,
oxygen and sulfur. The term "heteroaryl" does not include rings having
ring members of --O--O--, --O--S-- or --S--S--.

[0364] The term "heterocyclic", when used alone or in combination, means a
partially or fully saturated ring moiety containing one, two or even
three rings wherein such rings may be attached together in a fused
manner, formed from carbon atoms and including one or more heteroatoms
selected from N, O or S. Examples of saturated heterocyclic radicals
include saturated 3 to 6-membered heteromonocyclic groups containing 1 to
4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,
pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic
group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing
1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
Examples of partially saturated heterocyclyl radicals include
dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

[0367] The term "alkylamino" includes "N-alkylamino" where amino radicals
are independently substituted with one alkyl radical. Preferred
alkylamino radicals are "lower alkylamino" radicals having one to six
carbon atoms. Even more preferred are lower alkylamino radicals having
one to three carbon atoms. Examples of such lower alkylamino radicals
include N-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino
and the like.

[0368] The term "dialkylamino" includes "N,N-dialkylamino" where amino
radicals are independently substituted with two alkyl radicals. Preferred
alkylamino radicals are "lower alkylamino" radicals having one to six
carbon atoms. Even more preferred are lower alkylamino radicals having
one to three carbon atoms. Examples of such lower alkylamino radicals
include N,N-dimethylamino, N,N-diethylamino, and the like.

[0369] The term "carbonyl", whether used alone or with other terms, such
as "aminocarbonyl", denotes --(C═O)--. "Carbonyl" is also used herein
synonymously with the term "oxo".

[0370] The term "aminocarbonyl" denotes an amide group of the formula
--C(═O)NH2.

[0371] The term "alkylthio" or "thioalkoxy" embraces radicals containing a
linear or branched alkyl radical, of one to ten carbon atoms, attached to
a divalent sulfur atom. An example of "alkylthio" or "thioalkoxy" is
methylthio,(CH3S--).

[0372] The term "compounds of the invention" are intended to encompass
compounds of Formula I, which in turn encompasses compounds of Formula
II, as well as compounds of any sub-formulas thereof, such as Formulas
I-A, I-A-1, I-A-2, I-A-3, I-A-4, I-A-5, I-A-6, I-A-7, I-B, II-A and II-B.

[0373] The term "pharmaceutically-acceptable" when used with reference to
a compound of Formulas I-II, and sub-formulas thereof, is intended to
refer to a form of the compound that is safe for administration. For
example, a salt form, a solvate, a hydrate, a prodrug or derivative form
of a compound of Formulas I-II, which has been approved for mammalian
use, via oral ingestion or other routes of administration, by a governing
body or regulatory agency, such as the Food and Drug Administration (FDA)
of the United States, is pharmaceutically acceptable.

[0374] Included in the compounds of Formulas I-II, Formulas I-II, and
sub-formulas thereof, are the pharmaceutically acceptable salt forms of
the free-base compounds. The term "pharmaceutically-acceptable salts"
embraces salts commonly used to form alkali metal salts and to form
addition salts of free acids or free bases. As appreciated by those of
ordinary skill in the art, salts may be formed from ionic associations,
charge-charge interactions, covalent bonding, complexation, coordination,
etc. The nature of the salt is not critical, provided that it is
pharmaceutically acceptable.

[0376] Also, the basic nitrogen-containing groups can be quaternized with
such agents as lower alkyl halides, such as methyl, ethyl, propyl, and
butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl,
lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl
halides like benzyl and phenethyl bromides, and others. Water or
oil-soluble or dispersible products are thereby obtained.

[0377] Additional examples of such salts can be found in Berge et al., J.
Pharm. Sci., 66:1 (1977). Conventional methods may be used to form the
salts. For example, a phosphate salt of a compound of the invention may
be made by combining the desired compound free base in a desired solvent,
or combination of solvents, with phosphoric acid in a desired
stoichiometric amount, at a desired temperature, typically under heat
(depending upon the boiling point of the solvent). The salt can be
precipitated upon cooling (slow or fast) and may crystallize (i.e., if
crystalline in nature), as appreciated by those of ordinary skill in the
art. Multiple counter-ions may form the salts of the compounds of the
invention. Thus, hemi-, mono-, di, tri- and poly-salt forms of the
compounds of the present invention are also contemplated herein. For
example, the salt may eb a mono-ionic salt, di-ionic salt or tri-ionic
salt, such as mono- or di-hydrochloride salt, bis-methansulfonate salt or
a monofumarate salt. Similarly, hemi-, mono-, di, tri- and poly-hydrated
forms of the compounds, salts and derivatives thereof, are also
contemplated herein.

[0378] The term "derivative" is intended to encompass any salt of a
compound of this invention, any ester of a compound of this invention, or
any other compound, which upon administration to a patient is capable of
providing (directly or indirectly) a compound of this invention, or a
metabolite or residue thereof, characterized by the ability to the
ability to modulate an enzyme.

[0379] The term "pharmaceutically-acceptable derivative" as used herein,
denotes a derivative which is pharmaceutically acceptable.

[0380] The term "prodrug", as used herein, denotes a compound which upon
administration to a subject or patient is capable of providing (directly
or indirectly) a compound of this invention. Examples of prodrugs would
include esterified or hydroxylated compounds where the ester or hydroxyl
groups would cleave in vivo, such as in the gut, to produce a compound
according to Formula I-II. A "pharmaceutically-acceptable prodrug" as
used herein, denotes a prodrug which is pharmaceutically acceptable.
Pharmaceutically acceptable modifications to the compounds of Formula
I-IV are readily appreciated by those of ordinary skill in the art.

[0381] The compound(s) of Formulas I-II, and sub-formulas thereof, may be
used to treat a subject by administering the compound(s) as a
pharmaceutical composition. To this end, the compound(s) can be combined
with one or more excipients, including without limitation, carriers,
diluents or adjuvants to form a suitable composition, which is described
in more detail herein.

[0382] The term "excipient", as used herein, denotes any pharmaceutically
acceptable additive, carrier, adjuvant, or other suitable ingredient,
other than the active pharmaceutical ingredient (API), which is typically
included for formulation and/or administration purposes. "Diluent" and
"adjuvant" are defined hereinafter.

[0383] The terms "treat", "treating," "treatment," and "therapy" as used
herein refer to therapy, including without limitation, curative therapy,
prophylactic therapy, and preventative therapy. Prophylactic treatment
generally constitutes either preventing the onset of disorders altogether
or delaying the onset of a pre-clinically evident stage of disorders in
individuals.

[0384] The phrase "effective dosage amount" is intended to quantify the
amount of each agent, which will achieve the goal of improvement in
disorder severity and the frequency of incidence over treatment of each
agent by itself, while avoiding adverse side effects typically associated
with alternative therapies. Accordingly, this term is not limited to a
single dose, but may comprise multiple dosages required to bring about a
therapeutic or prophylactic response in the subject. For example,
"effective dosage amount" is not limited to a single capsule or tablet,
but may include more than one capsule or tablet, which is the dose
prescribed by a qualified physician or medical care giver to the subject.

[0385] The term "leaving group" (also denoted as "LG") generally refers to
groups that are displaceable by a nucleophile. Such leaving groups are
known in the art. Examples of leaving groups include, but are not limited
to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate),
sulfides (e.g., SCH3), N-hydroxsuccinimide, N-hydroxybenzotriazole,
and the like. Nucleophiles are species that are capable of attacking a
molecule at the point of attachment of the leaving group causing
displacement of the leaving group. Nucleophiles are known in the art.
Examples of nucleophilic groups include, but are not limited to, amines,
thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides,
amides, carbanions) and the like.

General Synthetic Procedures

[0386] The present invention further comprises procedures for the
preparation of compounds of Formulas I-II, and sub-formulas thereof. The
compounds of Formulas I-II can be synthesized according to the procedures
described in the following Schemes 1 and 2, wherein the substituents are
as defined for Formulas I-II above, except where further noted. The
synthetic methods described below are merely exemplary, and the compounds
of the invention may also be synthesized by alternate routes utilizing
alternative synthetic strategies, as appreciated by persons of ordinary
skill in the art.

[0460] Scheme 1 describes an exemplary method for preparing compounds 6 of
Formulas I-IV, wherein X is S, Y is CH2, A1 is CR6 and
R1, R4, R5, R6 and R8 are each H, respectively.
As shown, a bromo-benzoic acid 1 can be coupled to a bromo-phenol 2 using
a copper reagent in conjunction with a suitable base, such cesium
carbonate, under suitable conditions. The coupled ether 3 can then be
treated with an acid, such as sulfuric acid, to effect ring closure to
the corresponding bromo-xanthene 4. The ketone of xanthene 4 can be
converted to the corresponding spiro amino-thiazine 5 as shown under
suitable conditions, such as using vinyl magnesium chloride and thiourea
in the presence of an acid, such as HCl. Bromo-intermediate 5 (where
R2 is a desired group, such as methoxy) can be converted to desired
compounds 6 via coupling at the site of the bromide, such as by a Suzuki
or Suzuki-like aromatic-halogen exchange, which reaction generally
employs a boronic acid moiety, a palladium catalyst reagent and a base.

[0461] Alternatively, the ketone intermediate 4 may be functionalized with
the desired R7 group via a Suzuki or Suzuki-like coupling reaction,
as discussed further herein, to provide intermediate 5-A. The ketone of
intermediate 5-A may then be converted to the corresponding amino
dihydrothiazine product 6 using the conditions discussed above.

[0462] The boronic ester intermediates 7 may be prepared by methods
described in the following references: (1) PCT Int. Patent Appl. No. WO
2005073189, titled "Preparation of fused heteroaryl derivatives as p38
kinase inhibitors" or (2) PCT Int. Patent Appl. No. WO 2006094187, titled
"Preparation of phthalazine, aza- and diaza-phthalazine compounds as
protein kinase, especially p38 kinase, inhibitors for treating
inflammation and related conditions". Also, desired boronic acids may be
purchased commercially in catalogs, or specially made by the vendor or by
persons skilled in the art.

[0463] The Suzuki method is a reaction using a borane reagent, such as a
boronic acid 7 or ester such as a dioxaborolane (not shown), and a
suitable leaving group containing reagent, such as the Br-xanthene 5 (Br
is a suitable halogen leaving group "LG"). As appreciated to one of
ordinary skill in the art, Suzuki reactions also utilize a palladium
catalyst. Suitable palladium catalysts include, without limitation,
Pd(PPh3)4, Pd(OAc)2 or Pd(dppf)Cl2. Where LG is a
halide, the halide may be an iodide, a bromide or even a chloride.
Chloro-pyridyl rings (where A1═N) undergo Suzuki reactions in
the presence of Pd catalysts. Other LGs are also suitable. For example,
Suzuki couplings are known to occur with a sulfonate, such as
trifluoromethanesulfonate, as the leaving group. The Suzuki reaction
conditions may vary. For example, Suzuki reactions are generally run in
the presence of a suitable base such as a carbonate base, bicarbonate or
an acetate base, in a suitable solvent such as toluene, acetonitrile, DMF
or an aqueous-organic solvent combination or a biphasic system of
solvents. Further, the reaction may require heat depending upon the
particular bromide 5 and/or boronic acid or ester 7, as appreciated by
those skilled in the art. In addition, where the bromide is an aromatic
moiety, such as phenyl, the reaction may be complete in a short period of
time with heat.

[0464] Other coupling methods are known. For example metal catalized
coupling chemistry, such Stille, Kumada, Negishi coupling methods, and
the like, may be employed to the xanthene cores 5 to prepare desired
cyclic products 6. In addition, for compounds wherein X is S, the free
amino group may need to be protected for effective coupling reactions to
install either R2 or R7 groups, and later deprotected to afford
the final desired compounds 6, as appreciated by persons of ordinary
skill in the art.

##STR00019##

[0465] Desired compounds 13 of Formula I, and sub-formulas of II, III and
IV, wherein the R2 group is --OR8 may be made as generally
described in Scheme 2. As shown, bromo-methoxy intermediate 9 can be
O-d-methylate using known reagents, such as borontribromide to afford the
alcohol product 10. The bromide of alcohol 10 can be coupled as described
above in scheme 1 to provide the desired R7 group intermediate 11.
The alcohol of intermediate 11 can be functionalized as desired, such as
by alkylation as shown, by reaction with an alkyl halide in the presence
of a suitable base, such as cesium carbonate as shown, in suitable
solvents to afford the finally desired product 13.

[0466] "LG" in this instance is a "leaving group" which may be a halide
such as an iodide, bromide, chloride or fluoride. LG may also be a
non-halide moiety such as an alkylsulfonate or other known groups which
generally form an electrophilic species (E.sup.+). Coupling reactions
generally occur more readily in one or a combination of solvents and a
base. Suitable solvents include, without limitation, generally
non-nucleophilic, anhydrous solvents such as toluene, CH2Cl2,
THF, DMF, N,N-dimethylacetamide and the like. The solvent may range in
polarity, as appreciated by those skilled in the art. Suitable bases
include, for example, tertiary amine bases such as DIEA, TEA, carbonate
bases such as Na2CO3, K2CO3, Cs2CO3,
hydrides such as NaH, KH and the like, alkoxides such as NaOCH3, and
the like. The base itself may also serve as a solvent. These coupling
reactions are generally fast and conversion occurs typically in ambient
conditions. However, depending upon the particular substrate, such
reactions may require heat, as appreciated by those skilled in the art.

EXAMPLES

[0467] The Examples, described herein below, represent various exemplary
starting materials, intermediates and compounds of Formulas I-II, which
should assist in a better understanding and appreciation of the scope of
the present invention and of the various methods which may be used to
synthesize compounds of Formulas I-II. Starting materials and
intermediates used in the Examples herein may also be prepared using the
procedures described in co-pending U.S. patent application Ser. No.
12/558,426, filed Sep. 11, 2009, which specification and disclosure is
hereby incorporated herein by reference in its entirety. It should be
appreciated that the general methods above and specific examples below
are illustrative only, for the purpose of assistance and of understanding
the present invention, and should not be construed as limiting the scope
of the present invention in any manner.

Chromatography: Unless otherwise indicated, crude product-containing
residues were purified by passing the crude material or concentrate
through an ISCO brand silica gel column (pre-packed or individually
packed with SiO2) and eluting the product off the column with a
solvent gradient as indicated. For example a description of (330g
SiO2, 0-40% EtOAc/Hexane) means the product was obtained by elution
from the column packed with 330 gms of silica, with a suitable solvent
gradient, such as 0% to 40% EtOAc in hexanes.

Preparative HPLC Method:

[0468] Unless otherwise indicated, the compounds described herein were
purified via reverse phase HPLC using one of the following instruments:
Shimadzu, varian, Gilson; utilizing one of the following two HPLC
columns: (a) a Phenomenex Luna or (b) a Gemini column (5 micron or 10
micron, C18, 150×50 mm)

[0469] A typical run through the instrument included: eluting at 45 ml/min
with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water
(0.1% TFA) over 10 minutes; conditions can be varied to achieve optimal
separations.

Proton NMR Spectra:

[0470] Unless otherwise indicated, all 1H NMR spectra were run on a
Bruker series 300 MHz instrument or a Bruker series 400 MHz instrument.
Where so characterized, all observed protons are reported as
parts-per-million (ppm) downfield from tetramethylsilane (TMS) or other
internal reference in the appropriate solvent indicated.

Mass Spectra (MS)

[0471] Unless otherwise indicated, all mass spectral data for starting
materials, intermediates and/or exemplary compounds are reported as
mass/charge (m/z), having an (M+H.sup.+) molecular ion. The molecular ion
reported was obtained by electrospray detection method (commonly referred
to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrument instrument
or an Agilent 1100 series LC/MSD system. Compounds having an isotopic
atom, such as bromine and the like, are generally reported according to
the detected isotopic pattern, as appreciated by those skilled in the
art.

[0472] The compounds disclosed and described herein have been named using
either (1) the naming convention provided with Chem-Draw Ultra 8.0
software, available in Chem Office, or (2) by the ISIS database software
(Advanced Chemistry Design Labs or ACD software).

Example 1

Procedure A

##STR00020##

[0473] Synthesis of Intermediate 1

[0474] Step 1: A RBF equipped with a reflux condenser was charged with
2-bromo-5-methoxy benzoic acid (430 g, 1.8614 mol), 4-bromo phenol (322
g, 1.8614 mol), potassium carbonate (514.5 g, 3.7 228 mol) and
CuOTf-toluene complex (24.08 g, 0.04653 mol). EtOAc (9.0 ml 0.09679 mol,
0.052) and toluene (1.3 L) were carefully added portion wise. After
stirring at RT for 10 min, the mixture was heated to 50° C. for 30
min and then to 110° C. for 20 hrs. The reaction mixture was
cooled to RT and diluted with water and acidified with 2N HCl. The
reaction mixture was extracted with EtOAc (3.0×2 L) and filtered
through a pad of celite. The combined extracts were dried over sodium
sulfate and concentrated to provide 590 g of a brown solid that was
carried on without further purification. Step 2: Sulfuric acid (1.6 L)
was added to 2-(4-bromophenoxy)-5-methoxybenzoic acid (530 g, 1.6401mo1)
at RT. The resulting dark mixture was heated to 60° C. for 1 hour.
The brown solution was cooled to RT and poured onto ice while stirring.
The resulting tan precipitate was collected by filtration, washed
sequentially with water (2 L), 1N NaOH (2.0 L) and ethanol (800 mL). The
derived solid was suspended in 2 L of acetone and stiffed vigorously for
1 hour. The mixture was filtered and dried under a vacuum to afford 1.3
kg of 2-bromo-7-methoxy-9H-xanthen-9-one as a white solid.

Example 2

Procedure B

##STR00021##

[0475] Synthesis of Intermediate 2

[0476] Step 1: A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol),
5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate
(2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen
atmosphere. To this slurry were added copper (I) trifloromethanesulfonate
toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The
resulting suspension was heated to 105° C. and stirred for 2 h
before being cooled to RT. The toluene was decanted, and water (8 L) and
EtOAc (8 L) were added. The resulting mixture was stirred until the solid
was completely dissolved. The EtOAc layer was separated and the pH of the
aqueous layer was adjusted to pH 2˜3 with 6N HCl. The aqueous layer
was extracted with EtOAc (3×5 L). The combined organic layers were
dried over Na2SO4, filtered and concentrated to give 1.28 Kg of
5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid. This
material was used in next step without further purification. Step 2: A
mixture of compound 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid (1.28
Kg, 4.44 mol), DEA (461 mL, 4.44 mol), HOBT (600 g, 4.44 mol), DIPEA
(1.547 L, 8.88 mol) in anhydrous DCM (8 L) was cooled to 0° C. and
EDCI (851.2 g, 4.44 mol, 1 eq) was added. The mixture was stirred at
0° C. for 30 minutes and then at RT overnight. The reaction
mixture was washed with an aqueous, saturated solution of NaHCO3,
brine and water. The organic phase was separated, dried over MgSO4
and concentrated under reduced pressure. The resulting crude mixture was
purified by silica gel chromatography (5 to 20% ethyl acetate in hexane)
to afford 950 g of
5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide as a yellow oil.
Step 3: 5-Bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide (457.5
g, 1.23 mol, 1 eq) was dissolved in anhydrous THF (3 L) and cooled to
-78° C. To this solution was added a solution of LDA (2M in
heptane/THF/ethyl benzene, 2.25 L, 4.5 mol, 3.65 eq) maintaining the
temperature below -70° C. After the addition was complete, the
solution was stirred for additional 30 min at -78° C. The
acetone-dry ice bath was removed and the reaction was quenched with a
saturated aqueous solution of NH4Cl (1 L), maintaining the
temperature below 10° C. Another batch of
5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide (457.5 g) was
processed using the same protocol. The crude reaction mixtures from both
reactions were combined and the layers were separated. The aqueous layer
was extracted with ethyl acetate (3×5 L). The combined organic
layers were dried and passed through a pad of silica gel. The filtrate
was evaporated, and the residue was triturated with DCM to give 70 g of
7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one. The mother liquor was
evaporated and the solid thus obtained was purified by recrystallization
using DCM/hexanes to give 180 g of
7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one.

Example 3

Procedure C

##STR00022##

[0477] Synthesis of Intermediate 3

[0478] Step 1: A 3-neck 12 L flask equipped with an overhead stirrer,
thermometer, condenser and nitrogen inlet was charged with NaH (186.1 g,
4.653 mol) and DMF (1500 mL). The slurry was cooled to 0° C. and a
solution of 4-iodophenol (488.6 g, 2.221 mol) in DMF (1500 mL) and added.
The temperature of the reaction mixture was maintained below
25-30° C. during this addition. After complete addition, the
cooling bath was promptly removed and the mixture continued to stir at RT
for 1 h. 5-Bromo-2-chloronicotinic acid (500 g, 2.115 mol) was then added
to the slurry portion wise. The reaction mixture was heated to
115° C. overnight. The dark brown reaction mixture was cooled to
20° C. and diluted with water (2 L). The reaction mixture was
acidified using HOAc (845 ml). The black homogenous solution (pH=5) was
allowed to stir for 1 h at RT and poured slowly onto ice-water (20 L).
The slurry was filtered at RT, washed with water (2×2 L) and dried
in air to give 765 g of 5-Bromo-2-(4-iodophenoxy)-nicotinic acid as light
orange solid. Step 2: A 5 L 3-neck flask equipped with an overhead
stirrer, a thermometer and nitrogen inlet was charged with PPA (4 Kg,
1942 mL) (115% H3PO4) and heated to 115-120° C.
5-Bromo-2-(4-iodophenoxy)nicotinic acid (400 g, 952 mmol) was charged
portion wise to the hot PPA. The viscous mixture was then allowed to stir
overnight (16-18 h) at 115-120° C. The dark viscous mixture was
cooled to 60-65° C. and poured slowly onto a mixture of ice (3000
g) and water (2000 mL) under mechanical stirring. The light brown slurry
was allowed to stir overnight and filtered at RT. The wet cake was washed
with water (2×1000 mL) followed by IPA (1500 mL) and hexane
(2×1000 mL). The solid was dried to obtain 326.4 g of
3-Bromo-7-iodo-5H-chromeno[2,3-b]pyridine-5-one as a grey solid.

Example 4

Procedure D

##STR00023##

[0479] Synthesis of Intermediate 4

[0480] Step 1: A dry 100 L glass jacketed reactor equipped with an
addition funnel, reflux condenser, solids addition system and temperature
probe was charged with 2,5-dibromobenzoic acid (2685 g, 9.6 mol) and
copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30
L) and EtOAc (20 mL) were then charged, followed by
2-methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring
cesium carbonate (6258 g, 19.2 mol) was added in portions. The mixture
was heated to 90° C. for 4 hours. The mixture was cooled to
35° C. and water (15 L) was added. After 15 minutes of stirring
the phases were separated and the aqueous phase was washed with toluene
(7.5 L). With stirring, EtOAc (15.0 L) was added to the aqueous phase,
followed by 6 M HCl (5.6 L) keeping the internal temperature below
30° C. The layers were separated and the organics were dried over
magnesium sulfate. Filtration through a pad of celite and concentration
provided a solid that was reslurried in 915 mL of EtAOc and 9.2 L of
heptanes. Stirring was continued for 1 hour before the solids were
filtered and washed with heptanes. Drying provided 2560 g of
5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a cream colored
solid. Step 2: A dry 100 L glass jacketed reactor equipped with an
addition funnel, reflux condenser and temperature probe was charged with
5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (2340 g, 6.9 mol). TFA
(11.7 L) was carefully added followed by TFAA (1144 mL). Boron
trifluoride diethyl etherate (85 mL, 0.68 mol) was then carefully added.
Stirring was continued to 4 hours at which point the reaction was
transferred to another 100 L glass reactor containing 35.1 L of water
cooled to 0° C. The resulting slurry was allowed to warm to RT and
stir for 1 hour. The solids were filtered and washed with water (4.7 L)
and 3 N NaOH (2×3.5 L) and water (7 L). The solids were transferred
into a 22 L reactor and acetone (4.7 L) was added. The solids were
slurried for 1.5 hour and the filtered, washing well with acetone (4.7
L). An additional slurry with acetone (6.4 L @ 45° C.) provided
1310 g of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one as an off white
solid.

Example 5

Procedure E

##STR00024##

[0481] Synthesis of Intermediate 5

[0482] Step 1: A solution of i-Pr2NH (828 mL, 5.85 mol) in anhydrous
THF (1.3 L) was cooled to -10° C. n-BuLi (1.6 M in hexanes, 3660
mL, 5.85 mol) was added and the solution was stirred for 10 min at
0° C. The reaction mixture was cooled to -78° C. and a
solution of 2-chloro-6-fluoropyridine (700 g, 5.32 mol) in anhydrous THF
(1.3 L) was slowly added keeping the internal temperature below
-60° C. After the addition was complete, the reaction mixture was
stirred for an additional hour and then a solution of triisopropyl borate
(1221 mL, 5.32 mol) in anhydrous THF (620 mL) was added drop wise keeping
the internal temperature below -60° C. After the addition, the
reaction mixture was warmed to RT and stirred over night. Water (3 L) was
added and the mixture was stirred vigorously. The reaction mixture was
concentrated under reduced pressure. The residue was treated with a cold
aqueous solution of NaOH (10 M, 1610 mL, 16.0 mol) and 50% H2O2
(392 mL, 6.92 mol) and stirred over night (Note: the internal temperature
increased slowly from 5 to 60° C.). The reaction mixture was
quenched with ice and 4N HCl until pH of the mixture was ˜5. EtOAc
(5 L) was added and stirred well. After phase separation, the aqueous
layer was extracted with EtOAc (1.5 L×2). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to provide
6-chloro-2-fluoropyridin-3-ol as an off white solid. Step 2: A solution
of 6-chloro-2-fluoropyridin-3-ol (1.4 Kg, 9.49 mol) was dissolved in
acetone (13 L), and treated with K2CO3 (1574 g, 11.39 mol, 1.2
eq) and MOMCl (840 g, 10.44 mol, 1.1 eq). The mixture was heated at
60° C. for 2 hrs. After cooling to RT, the reaction mixture was
filtered to remove inorganic salts. The filtrate was concentrated under
reduced pressure. The residue was purified by flash column chromatography
(0-10% EtOAc/hexanes), affording
6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1496 g) as a colorless oil
in 80% yield over two steps. Step 3: A solution of i-Pr2NH (1100 mL,
7.72 mol) in anhydrous THF (3.5 L) was cooled to -10° C. n-BuLi
(2.5 M in hexanes, 3087 mL, 7.72 mol) was added drop wise and the
solution was stirred for 10 min at 0° C. The reaction mixture was
cooled to -78° C. and a solution of
6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1344 g, 7.02 mol) in
anhydrous THF (2 L) was added slowly, keeping the internal temperature
below -60° C. The resulting solution was stirred at -75° C.
for 1 hr. A solution of 5-bromo-2-fluorobenzaldehyde (1430 g, 7.02 mol)
in THF (1.7 L) was added drowise. After the addition was complete, the
reaction mixture was stirred at -75° C. for 30 min. The reaction
mixture was warmed to RT and quenched with saturated aqueous NH4Cl
solution (3 L). EtOAc (5 L) was added and the mixture was stirred
vigorously. After phase separation, the aqueous layer was extracted with
EtOAc (3 L×2). The combined organics were washed with brine and
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by column chromatography
(0-10% EtOAc/hexanes) to provide 2128 g of
(5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl-
)methanol as a light yellow solid. Step 4: A solution of KBr (65.1 g, 0.55
mol) in water (5.9 L) was added to a solution of
(5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl-
)methanol (2157 g, 5.47 mol) in DCM (5.9 L). The resulting biphasic
mixture was cooled to 5° C. TEMPO (8.6 g, 0.055 mol) was added and
the reaction mixture was stirred for 5 min. A solution of NaHCO3
(106 g, 1.26 mol, 0.23 eq) in bleach (6170 mL, 6.01 mol, 1.1 eq) was
added slowly keeping the internal temperature below 10° C. After
the addition was completed, the organic phase was separated. The aqueous
layer was extracted with DCM (4 L×2). The combined organic layers
were washed with 5% aqueous solution of sodium metabisulfite (6
L×1), brine (3 L×1) and dried over anhydrous
Na2SO4. The solution was concentrated under reduced pressure to
give 2200 g of
(5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl-
)methanone as a yellow solid. Step 5: To a solution of
(5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl-
)methanone (1200 g, 3.06 mol) in THF (4.8 L) was added 6 N aqueous HCl
solution (1600 mL, 9.17 mol) and the reaction mixture was heated to
60° C. for 5 hours. The reaction mixture was cooled to RT, and
then water (3 L) and EtOAc (3 L) were added. After the phases were
separated, the aqueous layer was extracted with EtOAc (3 L×2). The
combined organic layers was washed with brine (2 L×1) and dried
over Na2SO4. The solution was concentrated under reduced
pressure. The residue was dissolved in hot MTBE (˜700 mL). The
solution was triturated with hexanes until a solid began to precipitate.
The slurry was cooled to RT overnight. The solid was filtered, washed
with hexanes (500 mL×2), and dried to give 821 g of
(5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-hydroxypyridin-4-yl)methanon-
e as a yellow solid. Step 6: A solution of
(5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-hydroxypyridin-4-yl)methanon-
e (730 g, 2.10 mol) in dioxane (6 L) was treated with Cs2CO3
(1024 g, 3.14 mol). The reaction mixture was heated to 100° C. for
5 hours and then cooled to RT. Water (9 L) was added and the mixture was
stirred vigorously. The resulting solids were filtered, washed with water
(1 L×2), hexanes (1 L×1), and EtOAc (700 mL) to provide 602 g
of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one as a light
yellow solid.

Example 6

Procedure F

##STR00025##

[0483] Synthesis of Intermediate 6

[0484] Step 1: A RBF equipped with a reflux condenser was charged with
4-bromophenol (15.5 g, 89.4 mmol), 2,5-diiodobenzoic acid (25.700 g, 68.7
mmol), EtOAc (0.337 ml, 3.44 mmol), and toluene (100 mL).
Cs2CO3 (44.8 g, 137 mmol) was carefully added portion-wise.
After stirring at RT for 1 min, the mixture was heated to 50° C.
for 40 min and then heated to 100° C. for 20 hrs. The reaction
mixture was allowed to cool to RT. The mixture was filtered through
Celite and the solids were washed with EtOAc. The filtrate was diluted
with water (200 mL), acidified with 2N HCl (300 mL), and extracted with
EtOAc (4×500 mL). The organic extract was washed with brine and
dried over sodium sulfate. The organic fraction was concentrated under
reduced pressure to afford crude 2-(4-bromophenoxy)-5-iodobenzoic acid
(31.1 g) as a tan oil that solidified upon standing. Step 2:
H2SO4 (73.3 ml, 1375 mmol) was added to
2-(4-bromophenoxy)-5-iodobenzoic acid (28.800 g, 68.7 mmol) at rt. The
resulting dark mixture was heated to 60° C. for 45 minutes. The
brown solution was poured slowly onto ice-water (1 L) with stirring. The
resulting tan precipitant was collected by filtration, washed with water
a 1 N solution of NaOH, again with water, and dried under reduced
pressure to afford 2-bromo-7-iodo-9H-xanthen-9-one (23.4 g) as a tan
solid that was used without further purification.

Example 7

Procedure G

##STR00026##

[0485] Synthesis of Intermediate 7

[0486] A solution of n-butyllithium (2.7N in heptanes; 165 mL, 445 mmol)
in THF (300 mL) was cooled to -78° C. and treated with
2,2,6,6-tetramethylpiperidine (77 mL, 456 mmol). The reaction mixture was
allowed to stir for 30 minutes. A solution of 5-chloro-2-fluoropyridine
(50.0 g, 380 mmol) in THF (200 mL) was added drop wise over 30 minutes.
After stirring for an additional 30 minutes, the reaction mixture was
quenched by bubbling CO2 through the reaction mixture for 10
minutes. The reaction mixture was allowed to warm to RT, and CO2 was
bubbled through for an additional 30 minutes. The reaction mixture was
then concentrated under reduced pressure and dissolved in DMF (400 mL).
4-Bromo-3-fluorophenol (72.6 g, 380 mmol) was added, followed by
potassium carbonate (68.3 g, 494 mmol). The reaction mixture was heated
to 120° C. overnight. The reaction mixture was diluted with EtOAc
and washed with 4N HCl. The organic layer was separated, washed with
water and dried over MgSO4. The solvent was removed under reduced
pressure. The crude residue was dissolved in Eaton's Reagent (700 mL,
54.0 g, 380 mmol) and the reaction mixture was heated to 120° C.
overnight. The reaction mixture was poured onto a mixture of ice and
MeOH. The resulting solid was filtered off and washed with water. The
solid was suspended in a mixture of MeOH (100 mL) and cyclopropyl methyl
ether (200 mL) and filtered off. The grey solid was washed with hexanes
and dried yielding
7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-one (53.76 g, 164
mmol, 43.0% yield) as a ˜4:1 mixture of isomers.

Example 8

Procedure H

##STR00027##

[0487] Synthesis of Intermediate 8

[0488] Step 1: A flask was charged with 2,4-dibromophenol (50.4 g, 200
mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The
suspension was stirred at RT for 30 minutes and then treated dropwise
with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the
mixture was filtered and the filtrate was partitioned between EtOAc and
water. The organic phase was separated, washed with water, aqueous
saturated NaHCO3 and brine. The organic phase was dried over
MgSO4 and the solvent was removed under reduced pressure to afford
54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next
step without further purification. Step 2: A solution of
2,4-dibromo-1-(methoxymethoxy)benzene (40.5 g, 137 mmol) in Et2O
(140 mL) was cooled to -78° C. and treated with n-BuLi (2.5M in
hexanes; 60.2 mL, 151 mmol) under nitrogen atmosphere. After 30 minutes a
solution of diethyl oxalate (27.9 mL, 205 mmol) in Et2O (20 mL) was
added dropwise. The reaction mixture was stirred for 45 minutes at that
temperature then quenched cold with saturated ammonium chloride solution.
The mixture was partitioned between Et2O and water. The organic
phase was separated, washed with water, brine, then dried over
MgSO4. The solvent was removed under reduced pressure to afford 49 g
of ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate, which was
used in the next step without further purification. Step 3: A flask was
charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and
neopentylzinc (II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added
under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes
and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15
mmol) was added in one portion. The reaction mixture was quenched with
saturated aqueous ammonium chloride after 8 h. The reaction was
partitioned between EtOAc and water. The organic phase was separated,
washed with NH4Cl, water and brine. The organic phase was dried over
MgSO4 and the solvent was removed under reduced pressure. The crude
material was purified by silica gel chromatography (10-30% EtOAc/hexane)
to provide 0.675 g (S)-ethyl
2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.

Example 9

Procedure I

##STR00028##

[0489] Synthesis of Intermediates 9, 10, 10A and 10B

[0490] Step 1: A 500-mL RBF was charged with
7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (12.3789 g, 39.9 mmol),
trimethylsulfonium iodide (8.95 g, 43.9 mmol), and DMSO (199 mL). The
resulting slurry was stirred vigorously for 5 minutes leading to a tan
slurry before potassium 2-methylpropan-2-olate (4.92 g, 43.9 mmol) was
added in one portion. The resulting reddish orange solution was
maintained at rt for 2 hours at which time azidotrimethylsilane (10.49
mL, 80 mmol) was added in one portion. The heterogeneous mixture became
homogeneous after 2-3 hours. The solution was maintained at RT overnight
before being diluted with EtOAc and transferred to a separatory funnel
containing saturated NaHCO3 (500 mL). The layers were separated and
the aqueous layer was extracted with EtOAc (3×250 mL). The combined
organic layers were sequentially washed with water and brine and dried
over sodium sulfate. The solution was concentrated in vacuo to provide an
orange oil that was evaporated from DCM (3×250 mL) to provide
5-azido-7-bromo-3-chloro-5-((trimethylsilyloxy)methyl)-5H-chromeno[2,3-c]-
pyridine which was carried on without further purification. A solution of
the derived foam in THF (250 mL) was cooled to 0° C. and LAH (2M
in THF) (39.9 mL, 80 mmol) was. The reaction was maintained at 0°
C. for 2 hours then allowed to warm to RT for 30 minutes. The reaction
was diluted with 150 mL of THF and quenched by the addition of sodium
sulfate decahydrate (38.5 g, 120 mmol). After the addition was complete
the slurry was stirred at RT for 1.5 hours before being filtered through
a pad of celite. The filter pad was washed with THF. The filtrate was
concentrated under vacuum to give a brown foam. The foam was concentrated
from DCM twise and left under vacuum overnight. The solid was taken up in
DCM (75 mL) and heated to boiling for 1 minute. The mixture was cooled to
RT, and then placed in the fridge for 1 hour. The solid was filtered,
washed with DCM (50 mL) and dried to provide
(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (8.94
g) as a light orange solid. Step 2: A 4-neck 3000-mL RBF with a
mechanical stirrer was charged with
(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (29.43
g, 86 mmol), tetrabutylammonium hydrogen sulfate (5.85 g, 17.23 mmol),
THF (431 mL), and bromoacetonitrile (30.0 mL, 431 mmol) to give a clear,
brown solution. The resulting solution was stirred vigorously for 5 min,
then a 2N aq. solution of NaOH (431 mL, 862 mmol) was added in one
portion. The mixture was stirred overnight and concentrated under vacuum.
The remaining material was partitioned between EtOAc (500 mL) and water
(500 mL). The layers were separated and the aqueous layer was extracted
with EtOAc (2×250 mL). The combined organic layers were washed with
brine and dried over magnesium sulfate. The solvent was removed under
reduced pressure. The residue was taken up in DCM and filtered through a
short pad of silica gel. The filtrate was concentrated and purified by
silica gel chromatography (0.5% MeOH/DCM) to provide
2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)aceto-
nitrile. Step 3: A flask was charged with
2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)aceto-
nitrile (21 g, 55.2 mmol), dioxane (460 mL) and HCl (4M in dioxane) (55.2
mL, 221 mmol) under nitrogen atmosphere. The reaction mixture was heated
to 100° C. overnight. The mixture was cooled to RT and filtered.
The filter cake was washed sequentially with dioxane and ether. The
collected material was dried to give 15.72 g of a cream-colored solid,
which was dissolved in DCM (100 mL) and saturated aqueous sodium
bicarbonate (750 mL). The mixture was extracted with DCM (2×250 mL)
and EtOAc (2×250 mL). The combined organic extracts were dried over
sodium sulfate and concentrated to give
7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxa-
zin]-5'-amine (Intermediate 1, 14.63 g) as an off-white solid. Step 4:
7-Bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxa-
zin]-5'-amine was chromatographed using supercritical CO2 (additives
25% MeOH with 0.2% DEA) on a Chiralpak AD-H column (50×150 mm, 5
μm) eluting at a flow rate 300 ml/min (100 bar pressure, 40° C.
column temperature). The first peak (retention time=1.6 min) provided
(R)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4-
]oxazin]-5'-amine (example 9B; intermediate 10A; >99% ee), and the
second peak (retention time=2.4 min) provided
(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4-
]oxazin]-5'-amine (example 9A; intermediate 10B; >99% ee).

Example 10

Procedure J

##STR00029##

[0491] Synthesis of Intermediates 11, 11A and 11B

[0492] Step 1: To a suspension of
3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-one (20.00 g, 49.8 mmol) and
trimethylsulfonium iodide (11.17 g, 54.7 mmol) in 250 mL DMSO under
nitrogen atmosphere was added lithium tert-butoxide [1N in heptane (54.7
mL, 54.7 mmol)] drop wise over 40 minutes. After stirring for an
additional 30 minutes, trimethylsilylazide (13.21 mL, 100 mmol) was
added. After stirring for an additional hour, the reaction mixture was
concentrated under reduced pressure. The remaining solution was diluted
with water. The resulting solid was filtered off and washed with water.
The solid was dissolved in 2-MeTHF, dried over MgSO4 and
concentrated. The crude residue was dissolved in 200 mL THF, cooled to
0° C. and treated with LAH (1.888 g, 49.8 mmol). After stirring
for 30 minutes, the cooling bath was removed, and the reaction mixture
was allowed to stir for an additional 30 minutes. The reaction mixture
was then cooled to 0° C. and quenched with sodium sulfate
decahydrate (32.1 g, 100 mmol). The reaction mixture was vigorously
stirred for one hour, filtered through a plug of celite and concentrated.
Purification of the crude residue by column chromatography [0-80% (95:5
EtOAc/MeOH)/DCM] gave
(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methanol (8.80 g,
20.32 mmol, 40.8% yield). Step 2: A solution of
(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methanol (10.00 g,
23.09 mmol) and bromoacetonitrile (12.06 mL, 173 mmol) in 25 mL THF was
heated to 40° C. Lithium tert-butoxide [1N in THF (173 mL, 173
mmol)]was added drop wise via addition funnel over 5 hours. After
completed addition, the reaction mixture was concentrated. The residue
was purified by column chromatography [0-80% (95:5 EtOAc/MeOH)/heptane]
to yield 2-((5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methox-
y)acetonitrile (5.58 g, 11.82 mmol, 51.2% yield). Step 3: A solution of
2-((5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)methoxy)acetoni-
trile (5.58 g, 11.82 mmol) in 100 mL 2-MeTHF under nitrogen atmosphere was
treated with trimethylaluminum [2N in heptane (7.98 mL, 15.96 mmol)].
After stirring for 10 minutes at RT, the reaction mixture was heated to
80° C. for 90 minutes. The reaction mixture was cooled to RT and
quenched with MeOH. The reaction mixture was treated with saturated
Rochelle's salt solution and vigorously stirred for an additional hour.
The organic layer was separated, washed with brine, dried over MgSO4
and concentrated under reduced pressure. Purification of the crude
residue by column chromatography [0-80% (90:10:1 DCM/MeOH/NH4OH)/DCM]
gave 3-bromo-7-iodo-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]-
oxazin]-5'-amine (Intermediate 2, 2.97 g). Step 4: Intermediates
(R)-3-bromo-7-iodo-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]o-
xazin]-5'-amine (11A) and
(S)-3-bromo-7-iodo-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]o-
xazin]-5'-amine (11B) were obtained form racemic
3-bromo-7-iodo-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazi-
n]-5'-amine using similar chiral separation conditions as described herein
for intermediate 10.

Example 11

Procedure K

##STR00030##

[0493] Synthesis of Intermediate 12

[0494] Step 1: A solution of
7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-one (10.00 g, 30.4
mmol) and trimethylsulfonium iodide (6.83 g, 33.5 mmol) in 150 mL DMSO
under argon atmosphere was treated with potassium tert-butoxide (3.76 g,
33.5 mmol) at rt. After 75 minutes, trimethylsilylazide (8.08 mL, 60.9
mmol) was added, and the reaction mixture was allowed to stir overnight.
The reaction mixture was then diluted with EtOAc and washed with water.
The suspension was filtered, and the filtrate was dried over MgSO4
and concentrated under reduced pressure. The crude residue was taken up
in 100 mL THF and cooled to 0° C. LAH (1.155 g, 30.4 mmol) was
added, and the reaction mixture was allowed to stir for 30 minutes. The
ice bath was removed, and the reaction mixture was allowed to stir for an
additional 30 minutes. The reaction mixture was then cooled back to
0° C. and quenched with sodium sulfate decahydrate (9.81 g, 30.4
mmol). After stirring for one hour, the reaction mixture was filtered
through celite and concentrated under reduced pressure. Purification of
the crude residue by column chromatography [0-80% (95:5 EtOAc/MeOH)/DCM]
gave (5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)me-
thanol (2.83 g, 7.87 mmol, 25.9% yield). Step 2: A solution of
(5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)methano-
l (2.83 g, 7.87 mmol) and bromoacetonitrile (5.48 mL, 79 mmol) in 16 mL
THF was heated to 40° C. and treated drop wise with lithium
tert-butoxide [1N in THF (79 mL, 79 mmol)] over a time period of 4 hours.
After completed addition the reaction mixture was concentrated under
reduced pressure. Purification of the crude residue by column
chromatography [0-40% (95:5 EtOAc/MeOH)/DCM] gave
2-45-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)metho-
xy)acetonitrile (1.362 g, 3.42 mmol, 43.4% yield). Step 3: To a solution
of 2-((5-amino-7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3-b]pyridin-5-yl)m-
ethoxy)acetonitrile (1.363 g, 3.42 mmol) in 10 mL 2-MeTHF under nitrogen
atmosphere was added trimethylaluminum [2N in heptane (3.42 mL, 6.84
mmol)]. After stirring for 10 minutes, the reaction mixture was heated to
80° C. overnight. The reaction mixture was then allowed to cool to
RT, and quenched with MeOH. Saturated Rochelle's salt solution was added,
and the reaction mixture was vigorously stirred for an additional hour.
The organic layer was separated, washed with brine, dried over MgSO4
and concentrated under reduced pressure. Purification of the crude
residue by column chromatography [0-80% (90:10:1 DCM/MeOH/NH4OH)/DCM]
gave 7-bromo-3-chloro-8-fluoro-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-
-5,3'-[1,4]oxazin]-5'-amine (0.422 g, 1.059 mmol, 31.0% yield).

Example 12

Procedure L

##STR00031##

[0495] Synthesis of Intermediates 13, 13A and 13B

[0496] Step 1: To a suspension of
7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (25.00 g, 77 mmol) and
trimethylsulfonium iodide (23.68 g, 116 mmol) in DMSO (130 mL)/THF (130
mL) was added drop wise potassium tert-butoxide (1M in THF) (116 mL, 116
mmol). After 15 min at RT trimethylsilyl azide (20.54 mL, 155 mmol) was
added. The reaction mixture was stirred for additional 40 minutes and
then quenched by addition of 100 ml of saturated aqueous sodium
bicarbonate. After stirring for 10 minutes EtOAc (100 ml) and water (100
ml were added and the layers were separated. The organic layer was washed
with water (3×100 ml), brine (100 ml) and dried over MgSO4.
The solvent was removed under reduced pressure to obtain a yellow residue
which was dissolved in 250 ml THF. The solution was cooled to 0°
C. and LAH (1 M in THF, 108 mL, 108 mmol) was added drop wise. After 5
minutes at 0° C. the reaction mixture was allowed to warm to RT.
The reaction mixture was cooled again to 0° C. and sodium sulfate
decahydrate (21.98 g, 155 mmol) was added portion wise. The mixture was
stirred for 5 minutes and diluted with 100 ml EtOAc. The reaction mixture
was filtered through a pad of Celite and the filter cake was washed with
EtOAc (100 ml). The filtrate was concentrated under reduced pressure to
obtain a yellow foam which was re-crystallized from DCM to afford
(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol as a white
solid. Step 2: A solution of
(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol (9.83 g,
27.8 mmol) in THF (46.3 mL) was sequentially treated with lithium
t-butoxide (1 M in THF) (30.5 mL, 30.5 mmol) and 2-bromoacetonitrile
(2.90 mL, 41.6 mmol) at RT. After 2.5 hours reaction time, additional 0.5
equivalent lithium t-butoxide and 2-bromoacetonitrile (1.5 mL) were
added. After 4 hours reaction time, an additional 0.25 equivalent lithium
t-butoxide and bromoacetonitrile (0.75 mL) were added. After 5 hours
reaction time another 0.25 equivalent of lithium t-butoxide and
bromoacetonitrile (0.75 mL) were added to the mixture. Water (100 ml) was
added and solvents were removed under reduced pressure. The aqueous
residue was filtered, the solid was washed twice with water, dried under
reduced pressure and re-suspended in ethanol. The solid was filtered off,
washed with ethanol and dried under reduced pressure to afford
2-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)acetonitri-
le. Step 3: To a solution of
2-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)acetonitri-
le (7.72 g, 19.63 mmol) in DCE (115 mL) was added trimethylaluminum (2M in
toluene) (19.63 mL, 39.3 mmol) at RT. The reaction mixture was stirred
for 10 min at RT and then heated to 75° C. for 1 hour. The
reaction mixture was cooled to RT and quenched with sodium sulfate
decahydrate. The reaction mixture was vigorously stirred for 30 minutes,
diluted with EtOAc and stirred overnight. The mixture was filtered
through a pad of celite and filter cake was washed with EtOAc. The
solvent was removed under reduced pressure to obtain an oily residue
which crystallized to give
7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-
-5-amine (7.49 g, 19.05 mmol, 97% yield) as a cream-colored solid. Step 4:
Intermediates
(R)-7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (13A) and
(S)-7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (13B) were obtained from racemic product,
7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-
-5-amine (Intermediate 13) using similar chiral separation conditions as
described herein for intermediate 10.

Example 13

Procedure M

##STR00032##

[0497] Synthesis of Intermediate 14

[0498] Step 1: To a solution of vinylmagnesium chloride (6.86 mL, 10.97
mmol) at -78° C. under nitrogen atmosphere was added drop wise a
solution of 2-bromo-7-iodo-9H-xanthen-9-one (2.00 g, 4.99 mmol) in THF
(30 mL). The reaction mixture was allowed to slowly warm to -10°
C., then the reaction was quenched with saturated NH4Cl. The mixture
was extracted with EtOAc followed by a solvent mixture of CHCl3:
i-PrOH (3:1). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The crude
material was purified by filtration over silica gel (10% EtOAc/hexane) to
give 2.14 g of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol as a white solid.
Step 2: To a solution of 2-bromo-7-iodo-9-vinyl-9H-xanthen-9-ol (0.50 g,
1.16 mmol) and thiourea (0.18 g, 2.33 mmol) in acetic acid (2.00 mL) was
added TFA (4.00 mL). The reaction mixture was stirred at RT overnight.
The reaction mixture was concentrated under reduced pressure and
extracted with EtOAc, followed by a solvent mixture of CHCl3: i-PrOH
(3:1). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by chromatography
(10%-100% EtOAc/hexane) to provide 0.36 g of
2'-bromo-7'-iodo-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthen]-2-amine as
a light yellow solid.

Example 14

Procedure N

##STR00033##

[0499] Synthesis of Intermediates 15, 15A and 15B

[0500] Step 1: A suspension of
7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (20 g, 60.9
mmol), (R)-2-methyl-2-propanesulfinamide (14.76 g, 122 mmol), and
titanium (IV) ethoxide (25.2 mL, 122 mmol) in THF (250 mL) was heated to
70° C. for 24 h. Additional (R)-2-methyl-2-propanesulfinamide (1.0
equiv) and titanium (IV) ethoxide (1.0 equiv) were added and the reaction
mixture was heated for additional 24 h. Additional
(R)-2-methyl-2-propanesulfinamide (1.0 equiv) and titanium (IV) ethoxide
(1.0 equiv) were added and the reaction mixture was heated for additional
8 h. The reaction mixture was quenched with brine (150 mL). The resulting
suspension was filtered through celite, and the filter cake was washed
with EtOAc. The filtrate was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by chromatography (100% hexanes) to afford racemic
N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methy-
lpropane-2-sulfinamide as an orange solid (15 g, 34.7 mmol, 57.1% yield).
Step 2: A solution of (2-tert-butoxy-2-oxoethyl)zinc (II) chloride (0.5M
in Et2O; 116 mL, 57.9 mmol) was cooled to 0° C. and a
solution of
(Z)-N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-m-
ethylpropane-2-sulfinamide (10 g, 23.16 mmol) in THF (100 mL) was added
drop wise. The resulting mixture was stirred at for 1 hour 0° C.
The reaction mixture was diluted with EtOAc and washed with aqueous
saturated solution of NH4Cl, followed by brine. The organic layer
was dried over Na2SO4, and concentrated under reduced pressure.
The obtained residue was purified by chromatography (0-20% EtOAc/hexanes)
to afford tert-butyl
2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno-
[2,3-c]pyridin-5-yl)acetate (7.5 g, 13.69 mmol, 59.1% yield) as a yellow
solid. Step 3: A solution of tert-butyl
2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno-
[2,3-c]pyridin-5-yl)acetate (7.5 g, 13.69 mmol) in dry THF (25 mL) was
cooled to -78° C. and diisobutylaluminum hydride (54.8 mL, 54.8
mmol) was added drop wise. The mixture was warmed to 0° C. and
kept at this temperature for 1 h. The reaction mixture was quenched with
a aqueous, saturated solution of Rochelle's salt and vigorously stirred
for 15 h. The organic layer was separated and the aqueous phase was
extracted with EtOAc. The combined organic layers were washed with brine
and dried over Na2SO4. The solution was concentrated under
reduced pressure. The residue was purified by chromatography (0-30%
EtOAc/hexanes) to afford
N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-
-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 89% yield) as a light yellow
solid. Step 4: To a solution of
N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-
-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 12.14 mmol) in dry MeOH (100
mL) at -20° C. was added a mixture of MeOH (80 mL)/acetylchloride
(20 ml). The resulting reaction mixture was stirred at -20° C. for
30 min and then quenched with 10% aqueous solution of Na2CO3.
DCM was added, the organic phase was separated and dried over
Na2SO4. The solution concentrated under reduced pressure and
the residue was purified by chromatography (0-50% EtOAc/hexanes) to
afford 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-y-
l)ethanol (4.0 g, 10.71 mmol, 88% yield) as a light yellow solid-foam.
Step 5: To a solution of
2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethan-
ol (4.2 g, 11.24 mmol) in MeOH (40 mL) was added potassium acetate (2.207
g, 22.48 mmol) followed by the drop wise addition of cyanogen bromide
(3.0 m solution in DCM; 4.50 mL, 13.49 mmol). The resulting reaction
mixture was stirred at RT for 17 h. The reaction mixture was concentrated
under reduced pressure, followed by the addition of 4.0 M HCl in dioxane
(15 mL). The reaction mixture was stirred at RT for 2 h. The reaction
mixture was concentrated under reduced pressure. The residue was
dissolved in DCM, washed with aqueous, saturated NaHCO3 solution and
brine. The solution was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by chromatography
(0-100% EtOAc/hexanes) to afford
7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-
-[1,3]oxazin]-2'-amine (Intermediate 11, 1.3 g, 3.26 mmol, 29.0% yield) as
a yellow solid. Step 6: Intermediates
(R)-7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine--
5,4'-[1,3]oxazin]-2'-amine (15A) and
(S)-7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine--
5,4'-[1,3]oxazin]-2'-amine (15B) were obtained from racemic
7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-
-[1,3]oxazin]-2'-amine using similar chiral separation conditions as
described herein for intermediate 10.

Example 15

Procedure O

##STR00034##

[0501] Synthesis of Intermediate 16

[0502] Step 1: A suspension of
7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (20 g, 60.9
mmol), (R)-2-methyl-2-propanesulfinamide (14.76 g, 122 mmol), and
titanium (IV) ethoxide (25.2 mL, 122 mmol) in THF (250 mL) was heated to
70° C. for 24 h. Additional (R)-2-methyl-2-propanesulfinamide (1.0
equiv) and titanium (IV) ethoxide (1.0 equiv) were added and the reaction
mixture was heated for additional 24 h. Additional
(R)-2-methyl-2-propanesulfinamide (1.0 equiv) and titanium (IV) ethoxide
(1.0 equiv) were added and the reaction mixture was heated for additional
8 h. The reaction mixture was quenched with brine (150 mL). The resulting
suspension was filtered through celite, and the filter cake was washed
with EtOAc. The filtrate was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by chromatography (100% hexanes) to afford racemic
N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methy-
lpropane-2-sulfinamide as an orange solid (15 g, 34.7 mmol, 57.1% yield).
Step 2: A solution of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5M
in Et2O; 116 mL, 57.9 mmol) was cooled to 0° C. and a
solution of
(Z)-N-(7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-m-
ethylpropane-2-sulfinamide (10 g, 23.16 mmol) in THF (100 mL) was added
drop wise. The resulting mixture was stirred at for 1 hour 0° C.
The reaction mixture was diluted with EtOAc and washed with aqueous
saturated solution of NH4Cl, followed by brine. The organic layer
was dried over Na2SO4, and concentrated under reduced pressure.
The obtained residue was purified by chromatography (0-20% EtOAc/hexanes)
to afford tert-butyl
2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno-
[2,3-c]pyridin-5-yl)acetate (7.5 g, 13.69 mmol, 59.1% yield) as a yellow
solid. Step 3: A solution of tert-butyl
2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno-
[2,3-c]pyridin-5-yl)acetate (7.5 g, 13.69 mmol) in dry THF (25 mL) was
cooled to -78° C. and diisobutylaluminum hydride (54.8 mL, 54.8
mmol) was added drop wise. The mixture was warmed to 0° C. and
kept at this temperature for 1 h. The reaction mixture was quenched with
a aqueous, saturated solution of Rochelle's salt and vigorously stirred
for 15 h. The organic layer was separated and the aqueous phase was
extracted with EtOAc. The combined organic layers were washed with brine
and dried over Na2SO4. The solution was concentrated under
reduced pressure. The residue was purified by chromatography (0-30%
EtOAc/hexanes) to afford
N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno
[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 89% yield) as
a light yellow solid. Step 4: To a solution of
2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethan-
ol (0.50 g, 1.338 mmol) in THF (10 mL) was added 4-nitrobenzoyl
isothiocyanate (0.306 g, 1.472 mmol) and the reaction mixture was stirred
at RT for 25 min. TEA (0.019 mL, 0.134 mmol) and
1,3-dicyclohexylcarbodiimide (0.304 g, 1.472 mmol) were added and the
reaction mixture was heated at 70° C. for 1.5 h. The reaction
mixture was allowed to warm to RT and concentrated under reduced
pressure. The residue was dissolved in MeOH (15 mL) and potassium
carbonate (0.555 g, 4.01 mmol) was added. The resulting mixture was
stirred at rt overnight. The reaction mixture was concentrated under
reduced pressure, washed with water and extracted with DCM. The combined
organic layers were dried over Na2SO4 and the solvent was
removed under reduced pressure. The residue was purified by
chromatography (0-40% EtOAc/hexanes) to afford
7-bromo-3-chloro-1-methoxy-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4-
'-[1,3]oxazin]-2'-amine (0.45 g, 1.096 mmol, 82% yield) as a yellow solid.

[0504] Step 1: To a solution of (2-tert-butoxy-2-oxoethyl)zinc(II)
chloride (0.5M in Et2O; 670 ml, 335 mmol) at 0° C. was added
drop wise a solution of
7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (55 g, 167
mmol) in THF (30 mL). The resulting reaction mixture was stirred at
0° C. for 1 h. The reaction mixture was quenched with aqueous,
saturated NH4Cl solution and extracted with EtOAc. The organic
extracts were dried over Na2SO4 and concentrated under reduced
pressure to afford tert-butyl
2-(7-bromo-3-chloro-1-fluoro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)ace-
tate (66.0 g, 148 mmol, 89% yield) as a yellow solid. Step 2: A solution
of tert-butyl
2-(7-bromo-3-chloro-1-fluoro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)ace-
tate (66 g, 148 mmol) in THF (200 mL) was cooled to -78° C.
followed by the drop wise addition of diisobutylaluminum hydride (1.0 M
solution in THF; 180 ml, 180 mmol). The resulting reaction mixture was
cooled to 0° C. and stirred for 2 h. The reaction mixture was
quenched with aqueous, saturated NH4Cl solution and extracted with
EtOAc. The combined organics were dried over Na2SO4 and
concentrated under reduced pressure. The obtained residue was purified by
chromatography (0-50% EtOAc/hexanes) to afford
7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5--
ol (48 g, 128 mmol, 86% yield) as a light yellow solid. Step: To a
solution of
7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5--
ol (48 g, 128 mmol) in THF (58 mL) were added azidotrimethylsilane (34.0
ml, 256 mmol) and boron trifluoride diethyl etherate (31.6 ml, 256 mmol).
The reaction mixture was heated to 60° C. for 15 h. Additional
azidotrimethylsilane (34.0 ml, 256 mmol) and boron trifluoride diethyl
etherate (31.6 ml, 256 mmol) were added and heating was continued for 3
h. The reaction mixture was quenched with aqueous, saturated NaHCO3
solution and extracted with EtOAc. The organic phase was separated, dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography (0-30% EtOAc/hexanes) to afford
2-(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethan-
ol (41 g, 103 mmol, 80% yield) as a pale yellow solid-foam. Step 4: To a
solution of LAH (1.0 M solution in tetrahydrafuran; 90 ml, 90 mmol) in
THF (50 mL) at rt was added drop wise a solution of
2-(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethan-
ol (24 g, 60.1 mmol) in THF (150 mL). The resulting mixture was stirred at
RT for 1 h. The reaction mixture was quenched with sodiumsulfate
decahydrate and stirred for 30 min. The mixture was filtered, the
filtrate was concentrated under reduced pressure and the residue was
purified by chromatography (0-50% EtOAc/hexanes) to afford
2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethan-
ol (16.5 g, 44.2 mmol) as a colorless oil. Step 5: To a solution of
2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethan-
ol (13 g, 34.8 mmol) in EtOH (50 mL) was added sodium acetate (5.71 g,
69.6 mmol) followed by the dropwise addition of cyanogen bromide (3.0M
solution in DCM; 13.92 ml, 41.8 mmol). The resulting mixture was stirred
at RT for 5 days. The reaction mixture was concentrated under reduced
pressure, washed with water extracted with DCM. The combined organic
layers were dried over Na2SO4, concentrated under reduced
pressure and azeotropically dried with toluene. The obtained residue was
dissolved in DCM and TFA (40 mL) was added to the solution. The resulting
mixture was stirred at RT for 30 min. The mixture was carefully quenched
with aqueous, saturated NaHCO3 solution and extracted with DCM. The
combined organics were dried over Na2SO4 and concentrated under
reduced pressure. The obtained residue was purified by chromatography
(0-3% MeOH/DCM) to afford
7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-
-[1,3]oxazin]-2'-amine (6.2 g, 15.55 mmol, 44.7% yield) as a light yellow
solid. Step 6: Intermediates
(R)-7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine--
5,4'-[1,3]oxazin]-2'-amine (15A) and
(S)-7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine--
5,4'-[1,3]oxazin]-2'-amine (15B) were obtained from racemic
7-bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-
-[1,3]oxazin]-2'-amine using similar chiral separation conditions as
described herein for intermediate 10.

Example 17

Procedure Q)

##STR00036##

[0505] Synthesis of Intermediates 17, 17A and 17B

[0506] Step 1: A suspension of
7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one (35 g, 107
mmol) in dry THF (210 mL) under nitrogen atmosphere was cooled to
0° C. and a solution of methylmagnesium bromide (3.0M solution in
diethyl ether; 107 mL, 320 mmol) in dry THF (70 mL) was added over 10
minutes via an addition funnel. After complete addition a saturated
aqueous solution of NH4Cl (125 mL) was added slowly to the stirring
reaction mixture, keeping the internal temperature below 30° C.
Water was added and the mixture was extracted twice with EtOAc. The
combined organic layers were dried over sodium sulfate before
concentrating under reduced pressure to afford
7-bromo-3-chloro-1-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (34.33
g, 100 mmol). Step 2: To a solution of
7-bromo-3-chloro-1-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (50 g,
145 mmol) in THF (300 mL) was added HCl in dioxane (4M, 19.95 mL, 80
mmol). The reaction was heated to 50° C. for 16 hours. The
reaction was cooled to RT and K2CO3 (30.1 g, 218 mmol) was
added. The reaction mixture was stirred for 30 minutes before filtering.
The filtrate was concentrated under reduced pressure and the resulting
crude material was washed with DCM. The solid was collected by filtration
to afford 7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridin-
e (33.0 g, 101 mmol, 69.6% yield). Step 3: To a solution of
7-bromo-3-chloro-1-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine (33 g,
101 mmol) in THF (450 mL) were added successively water (69.2 mL), iodine
(51.3 g, 202 mmol) and silver(II) oxide (46.8 g, 202 mmol) at RT. The
reaction mixture was stirred at RT for 10 minutes before adding
K2CO3 (41.9 g, 303 mmol). After 30 minutes, the reaction
mixture was diluted with EtOAc and filtered through a pad of celite. The
filter cake was washed with additional EtOAc. The combined filtrate was
concentrated under reduced pressure upon which a white solid
precipitated. The solid was filtered off. The filtrate was further
concentrated under reduced pressure to obtain a residue which was
triturated with ether to afford a white precipitate. The solid was
filtered off, combined with the first solid and dried under reduced
pressure to afford
7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,2'-oxirane]
(23.56 g, 68.8 mmol). Step 4: To a solution of
7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,2'-oxirane]
(23.5 g, 68.6 mmol) in DMF (600 mL) was added azidotrimethylsilane (54.6
mL, 412 mmol). The reaction mixture was stirred at RT for 6 hours.
Additional azidotrimethylsilane (54.6 mL, 412 mmol) was added and the
reaction was stirred at RT for 18 hours. The reaction mixture was diluted
with EtOAc and water. The organic layer was separated, washed
sequentially with a saturated aqueous LiCl solution and brine before
drying over sodium sulfate. The solution was concentrated under reduced
pressure to afford
(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methano-
l (26.12 g, 67.7 mmol, 99% yield). Step 5: A solution of
(5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methano-
l (25.1 g, 65.1 mmol) in THF (500 mL) was cooled to -10° C. and a
solution of LAH (1.0 M in THF; 65.1 mL, 65.1 mmol) was added drop wise
via an addition funnel over a time period of 1.5 hours. Upon complete
addition, the reaction mixture was stirred additional 20 min at
-10° C. The reaction mixture was quenched with the drop wise
addition of saturated aqueous potassium sodium tartarate solution (60
mL). The reaction was diluted with water and EtOAc. The organic layer was
separated, washed with brine and dried over sodium sulfate. The solvent
was removed under reduced pressure to afford
(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methano-
l (21.74 g, 60.5 mmol, 93% yield). Step 6: A 3-neck RBF was charged with
(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methano-
l (20.7 g, 57.6 mmol) and THF (10 mL). The flask was equipped with two
addition funnels which were charged with lithium tert-butoxide solution
(1.0M in THF; 98 mL, 98 mmol) and a solution of bromoacetonitrile (6.82
mL, 98 mmol) in THF (10 mL), respectively. The two solutions were added
simultaneously to the stirring solution at ambient temperature over a
time period of 3 hours. Upon complete addition, the addition funnels were
recharged with lithium tert-butoxide solution, 1.0 M in THF (98 mL, 98
mmol) and a solution of bromoacetonitrile (6.82 mL, 98 mmol) in THF (10
mL), respectively. The two solutions were added simultaneously to the
stirring solution at ambient temperature over a time period of 3 hours.
The reaction was quenched with saturated aqueous ammonium chloride
solution and stirred for 16 hours. The reaction was diluted with water
and EtOAc. The organic layer was separated and the aqueous layer was
extracted twice with EtOAc. The combined organic layers were washed with
brine and dried over sodium sulfate. The solution was concentrated under
reduced pressure, and the resulting black solid was triturated with ether
and filtered to afford a brown precipitate. The filtrate was further
concentrated and purified by chromatography (50-100% EtOAc/hexanes). The
solids obtained through trituration and purification by chromatography
were combined to afford
2-((5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)meth-
oxy)acetonitrile (17.9 g, 44.9 mmol). Step 7: A solution of
trimethylaluminum solution (2.0 M in toluene; 7.32 ml, 14.64 mmol) was
added drop wise to a suspension of
2-((5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)meth-
oxy)acetonitrile (3.89 g, 9.76 mmol) in DCE (14.00 ml) at RT under an
atmosphere of nitrogen. Upon complete addition, the reaction mixture was
heated to 70° C. for 10 minutes. The reaction mixture was cooled
to RT quenched with a saturated aqueous potassium sodium tartarate
solution. The reaction mixture was vigorously stirred for one hour before
diluting with EtOAc and water. The organic layer was separated, and the
aqueous layer was washed twice with additional EtOAc. The combined
organic layers were washed with brine, dried over sodium sulfate and
concentrated under reduced pressure. DCM and EtOAc were added to the
residue and the resulting solution was filtered. The filtrate was
concentrated under reduced pressure and purified by chromatography
(20-70% EtOAc/hexanes) to afford
7-bromo-3-chloro-1-fluoro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-
-[1,4]oxazin]-5'-amine (Intermediate 7, 1.539 g, 3.86 mmol, 37%). Step 8:
Intermediates
(R)-7-bromo-3-chloro-1-fluoro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine--
5,3'-[1,4]oxazin]-5'-amine (17B) and
(S)-7-bromo-3-chloro-1-fluoro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine--
5,3'-[1,4]oxazin]-5'-amine (17A) were obtained from racemic
7-bromo-3-chloro-1-fluoro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-
-[1,4]oxazin]-5'-amine using similar chiral separation conditions as
described herein for intermediate 10.

Example 18

Procedure R

##STR00037##

[0507] Synthesis of Intermediates 18, 18A and 18B

[0508] Step 1: A 3-neck RBF equipped with an addition funnel and reflux
condenser was charged with zinc dust (37.9 g, 580 mmol) and diethyl ether
(300 ml). Bromine (1.544 ml, 29.0 mmol) was added drop wise to the
stirring suspension at RT. After 5 minutes, ethyl 2-bromoacetate (32.3
ml, 290 mmol) was added drop wise via addition funnel over the time
period of 1 hour. The reaction mixture was heated to reflux for one hour.
7-Bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (30 g, 97 mmol) was
added in one portion followed by THF (200 ml). After stirring at
40° C. for 10 minutes, the reaction mixture was cooled to RT and
quenched with saturated aqueous ammonium chloride solution (250 mL). The
reaction mixture was stirred for 1 hour before diluting with EtOAc and
filtering through a pad of celite. The organic layer was separated,
washed with brine and dried over MgSO4. The solution was
concentrated under reduced pressure to afford ethyl
2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate
(40.3 g) which was used in the next step without further purification.
Step 2: To a solution of ethyl
2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate
(38.5 g, 97 mmol) in toluene (400 ml) was added azidotrimethylsilane
(38.4 ml, 290 mmol) followed by (diethyloxonio)trifluoroborate (24.48 ml,
193 mmol) under an atmosphere of nitrogen. The reaction mixture was
stirred at RT for 16 hours. The reaction mixture was quenched with MeOH
(200 mL) and diluted with EtOAc. The organic phase was separated, washed
with saturated aqueous sodium bicarbonate solution and brine. The organic
layer was dried over magnesium sulfate and concentrated under reduced
pressure to afford ethyl
2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.82
g) which was used in the next step without further purification. Step 3:
A solution of ethyl
2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.82
g, 96 mmol) in THF (400 ml) was cooled to 0° C. under nitrogen
atmosphere. A solution of LAH (1.0M solution in THF; 116 ml, 116 mmol)
was added drop wise at 0° C. over a time period of 90 minutes.
Upon complete addition, the reaction mixture was warmed to RT and stirred
for additional 10 minutes. The reaction mixture was quenched with sodium
sulfate decahydrate (50 g) and stirred for 20 minutes at RT. Celite was
added to the reaction mixture and the suspension was filtered. The
filtrate was concentrated under reduced pressure and the crude residue
was purified by chromatography [1-2% (2M ammonia in MeOH)/DCM] to afford
2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (17.3
g, 48.6 mmol, 50.5% yield). Step: To a solution of
2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (0.782
g, 2.199 mmol) in THF (15.27 ml) was added benzoyl isothiocyanate (0.325
ml, 2.419 mmol) at RT. The reaction mixture was stirred for 30 minutes
after which the reaction was concentrated to dryness under reduced
pressure. The residue was dissolved in ACN (15.27 ml) and triethylamine
(0.031 ml, 0.220 mmol) and dicyclohexylcarbodiimide (0.476 g, 2.309 mmol)
were added consecutively. The reaction mixture was heated to 80°
C. for 2 hours. The reaction mixture was cooled to RT and concentrated to
dryness under reduced pressure. The resulting residue was suspended in
MeOH (15.27 ml) and THF (3.05 ml). A solution of NaOH (1.0M in water;
10.67 ml, 11.0 mmol) was added and the reaction mixture was heated to
70° C. for 3 hours. The reaction mixture was cooled to RT and
concentrated under reduced pressure. The resulting residue was dissolved
in EtOAc and washed with water and brine. The organic layer was dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified chromatography [1-5% (2M ammonia in MeOH)/DCM] to
afford 7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[-
1,3]oxazin]-2'-amine (Intermediate 10, 0.492 g, 1.293 mmol, 58.8% yield).
Step 5: Intermediates
(R)-7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3-
]oxazin]-2'-amine (18A) and
(5)-7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3-
]oxazin]-2'-amine (18B) were obtained from racemic
7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxa-
zin]-2'-amine using similar chiral separation conditions as described
herein for intermediate 10.

Example 19

Procedure S)

##STR00038##

[0509] Synthesis of Intermediate 19

[0510] Step 1: A solution of
7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (3000 mg, 9.66 mmol) in
THF (70 mL) was cooled to -30° C. under nitrogen atmosphere.
Isopropenylmagnesium bromide, (0.5m solution in THF; 48.3 mL, 24.15 mmol)
was added dropwise. The reaction mixture was stirred for 30 min at
-30° C. Aqueous saturated ammoniumchloride solution was added,
followed by EtOAc. The organic phase was separated and dried over
MgSO4. The solvent was removed under reduced pressure to yield the
product as a light-yellow solid (3.2 g). The product was taken onto the
next reaction step without further purification. Step 2: To a solution of
7-bromo-3-chloro-5-(prop-1-en-2-yl)-5H-chromeno[2,3-c]pyridin-5-ol (3.2
g, 9.08 mmol) in THF (80 mL) was added a solution of borane-THF complex
(1.0M in THF; 72.6 mL, 72.6 mmol) at RT under nitrogen atmosphere. The
reaction mixture was allowed to stir at RT overnight. Water (10 mL) was
added, followed by 2 M NaOH (15 mL). Then hydrogen peroxide (35 wt. %
solution in H2O; 22.25 mL, 726 mmol) was added slowly. Et2O was
added, followed by water. The organic phase was separated, washed with
brine and dried over MgSO4. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography (5-30%
EtOAc/hexanes). The desired product
7-bromo-3-chloro-5-(1-hydroxypropan-2-yl)-5H-chromeno[2,3-c]pyridin-5-ol
(2.53 g, 6.83 mmol, 75% yield) was isolated as a white solid (1:1 mixture
of diastereoisomers). Step 3: Azidotrimethylsilane (1.432 mL, 10.79 mmol)
and borontriflouride etherate (1.368 mL, 10.79 mmol) were added
sequentially to a solution of
7-bromo-3-chloro-5-(1-hydroxypropan-2-yl)-5H-chromeno[2,3-c]pyridin-5-ol
(2000 mg, 5.40 mmol) in THF (50 mL). The reaction mixture was heated to
66° C. After 12 h reaction time, additional azidotrimethylsilane
(1.432 mL, 10.79 mmol) and borontriflouride etherate (1.368 mL, 10.79
mmol) were added and the reaction mixture was continued to be heated to
65° C. After 24 h reaction time, additional azidotrimethylsilane
(1.432 mL, 10.79 mmol) and borontriflouride etherate (1.368 mL, 10.79
mmol) were added and the reaction mixture was continued to be heated to
65° C. After 32 h reaction time, the reaction mixture was cooled
to rt and aqueous saturated bicarbonate solution was added carefully,
followed by EtOAc. The organic phase was separated and dried over
MgSO4. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography (10-55% EtOAc/hexanes).
2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)propan-1-ol
(1.32 g, 85% purity) was isolated of a white solid and taken onto the
next step without further purification. Step 4: A solution of
2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)propan-1-ol
(1300 mg, 3.29 mmol, 85% purity) in THF (10 mL) was cooled to 0°
C. under nitrogen atmosphere. LAH (1.0M solution in THF; 3.61 mL, 3.61
mmol) was added dropwise. A mixture of celite and
Na2SO4*10H2O was added. The reaction mixture was filtered,
the solvent was removed under reduced pressure and the residue was
purified by flash chromatography (10-50% EtOAc/hexanes) to afford the
desired product
2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)propan-1-ol
(0.85 g, 2.300 mmol, 70.0% yield) as a white solid. Step 5: To a
suspension of
2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)propan-1-ol
(0.85 g, 2.300 mmol) in EtOH (10 mL) was added anhydrous sodium acetate
(0.377 g, 4.60 mmol) followed by the drop wise addition of cyanogen
bromide (3.0M in CH2Cl2; 0.920 mL, 2.76 mmol). The suspension
was stirred at RT for 48 h. Additional cyanogen bromide (0.8 mL, 0.6 eq)
and NaOAc (180 mg, 1.0 eq) were added. The reaction mixture was allowed
to stir for 3 days at RT. The reaction mixture was concentrated under
reduced pressure, washed with water and extracted with DCM. The combined
organic layers were dried over MgSO4 and azeotropically dried with
toluene. A white solid was obtained which was suspended in DCM (15 mL).
Upon dropwise addition of TFA (2 mL) the reaction mixture turned clear
and yellow. The resulting mixture was stirred at RT for 20 min. The
solvent was removed under reduced pressure and aqueous saturated
NaHCO3 solution and CH2Cl2 were added. The suspension was
filtered and 7-bromo-3-chloro-5'-methyl-5',6'-dihydrospiro[chromeno
[2,3-c]pyridine-5,4'-[1,3]oxazin]-2'-amine was obtained as a white solid
(305 mg). The filtrate was transferred into a separatory funnel. The
organic phase was separated and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was purified by flash
chromatography to obtain additional
7-bromo-3-chloro-5'-methyl-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4-
'-[1,3]oxazin]-2'-amine (300 mg).

Example 20

Procedure T

##STR00039##

[0511] Synthesis of Intermediates 20, 20A and 20B

[0512] Step 1: To a suspension of
7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (20 g, 61.9 mmol) in
2-methyl-THF (300 mL) a solution of (2-tert-butoxy-2-oxoethyl)zinc(II)
chloride (0.5 M in Et2O; 186 mL, 93 mmol) was added at RT. The
mixture was stirred for 10 min at RT, and then heated to 45° C.
for 1 hour. The reaction mixture was cooled to RT and quenched with
aqueous, saturated NH4Cl (150 mL) and water (100 mL). The organic
layer was separated, washed with brine and filtered through the pad of
Celite. The solvent was removed under reduced pressure to yield as a
yellowish solid which was dissolved in of benzene (200 mL).
Azidotrimethylsilane (12.30 mL, 93 mmol) was added and the reaction
mixture was cooled to 5° C. Borontrifluoride etherate (7.84 mL,
61.9 mmol) was added drop wise. The reaction mixture was quenched by the
addition of MeOH (5 mL) and aqueous, saturated NaHCO3 solution (100
ml). The organic layer was separated, washed with brine, filtered through
Celite and concentrated under reduced pressure to afford a yellow
residue, which was dissolved in THF (300 mL). The solution was cooled to
0° C. and LAH (1M in THF; 93 mL, 93 mmol) was added drop wise at
this temperature. The reaction mixture was allowed to warm to RT and
quenched by the addition of sodium sulfate decahydrate (20 g). The
reaction mixture was stirred for 2 hrs at RT, then filtered through
celite. The filter cake was washed twice with EtOAc. The filtrate was
concentrated under reduced pressure and the residue was purified by
chromatography [5-50% DCM/MeOH/NH4OH (90:10:1)] in DCM to afford
2-(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)ethanol (10.99 g,
29.8 mmol). Step 2: To a solution of
2-(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)ethanol (7.17 g,
19.47 mmol) in THF (100 mL) was added 4-nitrobenzoyl isothiocyanate (4.26
g, 20.45 mmol). The reaction mixture was stirred for 30 min at RT. EDC
(5.60 g, 29.2 mmol) and TEA (0.543 ml, 3.89 mmol) were added sequentially
and the reaction mixture was heated to 70° C. for 1 hr. The
reaction mixture was cooled to RT and water (50 ml) was added. The
reaction mixture was stirred for 1 hr, upon which a precipitate formed,
which was filtered off and washed with water and MeOH. The solid was
dried to afford
N-(7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xanth-
ene]-2-yl)-4-nitrobenzamide (6.0 g, 11.06 mmol, 56.8% yield). Step 3: A
suspension of
N-(7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xanth-
ene]-2-yl)-4-nitrobenzamide (6.0 g, 11.06 mmol) in methanol (60 mL) was
heated to 65° C. NaOH (2 M solution) (48.7 ml, 97 mmol) was added
and the resulting mixture was heated to 65° C. for 4 hrs. The
reaction mixture was concentrated under reduced pressure, the precipitate
was filtered off, washed twice with water and dried to afford
7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xanthen]-
-2-amine (3.90 g, 9.92 mmol, 50.9% yield) as white solid. Step 4:
Intermediates
(R)-7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xant-
hen]-2-amine (20A) and
(S)-7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xant-
hen]-2-amine (20B) were obtained from racemic
7'-bromo-4'-fluoro-2'-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9'-xanthen]-
-2-amine using similar chiral separation conditions as described herein
for intermediate 10.

Example 21

Procedure U

##STR00040##

[0513] Synthesis of Intermediate 21

[0514] A vial was charged with
(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno
[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (Intermediate 1B, 1.0 g, 2.63
mmol) and DMSO (13.14 mL). Sodium methoxide (0.710 g, 13.14 mmol) was
added and the reaction mixture was heated to 80° C. for 2.5 hours.
The reaction mixture was cooled to RT and quenched with aqueous,
saturated ammonium chloride solution. Water and EtOAc were added, and the
organic layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine, dried over
sodium sulfate and concentrated under reduced pressure. The residue was
purified via column chromatography (0-100% EtOAc/hexanes) to afford
(S)-7-bromo-3-methoxy-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,-
4]oxazin]-5'-amine (Example 21A; 0.611 g, 1.624 mmol, 61.8% yield) as a
yellow solid.

Example 22

Procedure V

##STR00041##

[0515] Synthesis of Intermediate 22

[0516] Step 1: Bromine (0.072 ml, 1.4 mmol) was added to a suspension of
zinc dust (1.41 g, 21.57 mmol) in diethyl ether (25 ml) at RT. After 5
minutes, ethyl 2-bromoacetate (1.202 ml, 10.8 mmol) was added drop wise
over a time period of 10 minutes and the reaction mixture was heated to
reflux for 2 hours. 7-Bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (2
g, 6.44 mmol) was added in one portion, followed by THF (25.00 ml) and
the reaction mixture was heated to reflux for 30 minutes. The reaction
mixture was quenched with aqueous saturated NH4Cl solution (20 mL)
and water (20 mL) and stirred 30 min at RT. The solution was filtered and
the organic phase was separated. The solvent was removed under educed
pressure to afford ethyl
2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (2.5
g, 6.27 mmol, 97% yield). Step 2: To a solution of ethyl
2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (20
g, 50.2 mmol) in toluene (300 ml) was added azidotrimethylsilane (19.93
ml, 151 mmol, followed by (diethyloxonio)trifluoroborate (12.72 ml, 100
mmol). The mixture was stirred overnight at RT. The reaction mixture was
quenched with MeOH (200 mL) and diluted with EtOAc. The organic phase was
separated, washed with saturated aqueous sodium bicarbonate solution and
brine. The organic layer was dried over magnesium sulfate and
concentrated under reduced pressure to afford ethyl
2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (21 g,
49.6 mmol, 99% yield). Step 3: A solution of ethyl
2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (47 g,
111 mmol) in THF (600 ml) was cooled to 0° C. under nitrogen
atmosphere. A solution of LAH (1.0M in THF; 133 ml, 133 mmol) was added
drop wise at 0° C. Upon complete addition, the reaction mixture
was warmed to RT and stirred for additional 10 minutes. The reaction
mixture was quenched with sodium sulfate decahydrate (50 g) and stirred
for 1 hour at room temperature. The suspension was filtered over celite.
The filtrate was concentrated under reduced pressure and the crude
residue was purified by recrystallization from cold DCM with heptane to
afford 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol
(16 g, 45.0 mmol, 40.6% yield). Step 4: A reaction mixture of
2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (2.8
g, 7.87 mmol) and 4-nitrobenzoyl isothiocyanate (1.639 g, 7.87 mmol) in
THF (100 mL) was stirred at RT for 1 hour. The reaction mixture was then
concentrated under reduced pressure to afford
N-(7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-ylcarb-
amothioyl)-4-nitrobenzamide (5 g, 8.87 mmol). Step 5:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (2.84 ml, 21.28 mmol) was added
to a solution of
N-((7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)ca-
rbamothioyl)-4-nitrobenzamide (12 g, 21.28 mmol) in DCM (200 ml). The
reaction mixture was stirred at RT for 8 hours and then concentrated
under reduced pressure to 50% of its original volume. A precipitate
formed upon cooling which was filtered off, washed with DCM and then
dried under reduced pressure to afford
N-(7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]-
thiazin]-2'-yl)-4-nitrobenzamide hydrochloride (10.5 g, 18.03 mmol, 85%
yield) as an off white solid. Step 6: A 2 N NaOH solution (24.47 ml, 48.9
mmol) was added to a solution of
N-(7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]-
thiazin]-2'-yl)-4-nitrobenzamide hydrochloride (9.5 g, 16.32 mmol) in MeOH
(250 ml). The reaction mixture was heated to 65° C. for 3 hours.
The reaction mixture was diluted with water (300 mL), stirred for 10 min,
and then filtered. The solid was washed with water and dried under
reduced pressure to afford
7-bromo-3-chloro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]thi-
azin]-2'-amine (3.9 g, 9.83 mmol, 60.3% yield).

[0520] Step 1: To a suspension of tetraethoxytitanium (3.40 g, 14.93 mmol)
in THF (16.58 ml) was added
3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-one (2.00 g, 4.98 mmol). The
suspension was cooled to 0° C. and (2-ethoxy-2-oxoethyl)zinc(II)
bromide (149 ml, 14.93 mmol) was added drop wise. The reaction mixture
was allowed to warm to RT and stirred 1 h. The reaction mixture was
quenched with aqueous, half-saturated NaHCO3 solution (20 mL) and
stirred for 30 min. The solution was filtered through a pad of celite and
the filter cake was rinsed with EtOAc. The organic layer was separated
and concentrated under reduced pressure to afford ethyl
2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate as a
yellowish solid. Step 2: Azidotrimethylsilane (1.102 ml, 8.32 mmol) was
added to a suspension of ethyl
2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (2.33
g, 4.75 mmol) in toluene (31.7 ml). The reaction mixture was cooled to
0° C. and (diethyloxonio) trifluoroborate (0.753 ml, 5.94 mmol)
was added slowly. The reaction mixture was allowed to warm to RT. After
30 min, the reaction mixture was quenched with MeOH (5 mL) followed by
aqueous, saturated NaHCO3 solution (10 mL). The reaction mixture was
extracted twice with EtOAc. The combined organic phases were washed with
brine and dried over sodium sulfate. The solvent was removed under
reduced pressure to afford ethyl
2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate as a
yellow solid. Step 3: LAH (1M in THF; 6.12 ml, 6.12 mmol) was added
slowly to a -78 C cooled solution of ethyl
2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (2.10 g,
4.08 mmol) in THF (40.8 ml). The reaction mixture was stirred at
-78° C. for 15 min, and the reaction mixture was allowed to warm
to RT and stirred for additional 30 min. The reaction mixture was cooled
to 0° C., quenched with sodium sulfate decahydrate (2.90 g, 20.38
mmol) and allowed to stir 20 min. The solution was filtered through a pad
of celite, the filter cake was eluted with 10% MeOH/DCM and the filtrate
was concentrated. The residue was purified via flash chromatography
(0-25% EtOAc/CH2Cl2) to afford
2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol as a
yellow solid. Step 4: A solution of
2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (0.930
g, 2.080 mmol) in THF (20.80 ml) was added cooled to 0° C. and
solid 4-nitrobenzoyl isothiocyanate (0.442 g, 2.122 mmol) was added. The
reaction mixture was stirred at 0° C. for 20 min. The reaction
mixture was concentrated under reduced pressure to yield
N-((3-bromo-5-(2-hydroxyethyl)-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)carb-
amothioyl)-4-nitrobenzamide as a yellow solid. Step 5:
1-Chloro-n,n,2-trimethyl-1-propenylamine (0.556 ml, 4.16 mmol) was added
to a solution of
N-((3-bromo-5-(2-hydroxyethyl)-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)carb-
amothioyl)-4-nitrobenzamide (1.363 g, 2.080 mmol) in CH2Cl2 (7
ml) at 0° C. The reaction mixture was allowed to warm to RT and
stir for 2 h. The reaction mixture was quenched with aqueous, saturated
NaHCO3 solution (5 mL), and was further diluted with 10% MeOH/DCM
and 5 mL water and
N-(3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]th-
iazin]-2'-yl)-4-nitrobenzamide collected as a pink solid. Step 6: A
suspension of
N-(3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]th-
iazin]-2'-yl)-4-nitrobenzamide (0.906 g, 1.422 mmol) and lithium hydroxide
hydrate (0.179 g, 4.27 mmol) in MeOH (28.4 ml) was heated to reflux for 3
hours. The solvent was removed under reduced pressure to afford
3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]thiaz-
in]-2'-amine as a pink solid. Step 7: Aqueous, saturated NaHCO3
solution (7.6 ml, 7.11 mmol) and boc anhydride (3.3 ml, 14.22 mmol) were
added to a stirred suspension of
3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]thiaz-
in]-2'-amine (694 mg, 1.422 mmol) in dioxane (7 ml). The reaction mixture
was stirred for 16 h at RT. The reaction mixture was partitioned between
EtOAc (50 mL) and water (20 ml). The aqueous layer was separated and
extracted with EtOAc (1×10 mL). The combined organic extracts were
washed with brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified via flash chromatography
(0-25% EtOAc/CH2Cl2) to afford tert-butyl
(3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]thia-
zin]-2'-yl)carbamate a yellow solid.

Example 25

Procedure Y

##STR00044##

[0521] Synthesis of Intermediate 25

[0522] Step 1: 3-Bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-one (6.0 g,
14.93 mmol) was taken up in THF (150 mL). Neat tetraethoxytitanium (9.29
mL, 44.8 mmol) was added. An ether solution of
(2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5 M, 62.7 mL, 31.3 mmol)
was added via cannula. The reaction was stirred at 0° C. for 30
min, then was warmed to rt and stirred 30 min. Excess organozinc reagent
was quenched at 0° C. with 250 mL of half-saturated brine. The
mixture was filtered through Celite, rinsing the solid with EtOAc (700
mL). The resulting filtrate's organic layer was separated and extracted
further with saturated brine (50 mL), then was dried over sodium sulfate
and concentrated. The crude tert-butyl
2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (7.8
g) was used in the next step without further purification. Step 2: In a
1-L flask, the tert-butyl
2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (7.8
g, 15.05 mmol) was suspended in toluene (100 mL). Neat
azidotrimethylsilane (2.99 mL, 22.58 mmol) was added. The mixture was
cooled to 0° C., and BF3-etherate (2.098 mL, 16.56 mmol) was
added. The mixture was allowed to warm naturally in the ice bath. After
two hours, the mixture was quenched with MeOH (3 mL), then with
half-saturated aqueous NaHCO3 (100 mL). The residue was extracted with
10% MeOH-EtOAc (3×200 mL). The organics were combined, washed with
saturated brine (50 mL), dried over sodium sulfate and concentrated. The
crude tert-butyl
2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate was used
in the next step without further purification (7.27 g). Step 3: In a 1-L
flask, the tert-butyl
2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (7.27 g,
13.38 mmol) was suspended in THF (100 mL) and the suspension was cooled
to 0° C. A THF solution of LAH (1 M, 20.08 mL, 20.08 mmol) was
added. After 30 min, the reaction mixture was quenched with careful
addition of water (0.75 mL), 4 M aqueous NaOH (2.2 mL), and water (0.75
mL). The mixture was filtered through Celite, rinsing with THF (60 mL),
then with EtOAc (150 mL). The combined filtrate was concentrated. The
residue was purified through silica gel (400 mL) which had been
deactivated with Et3N (40 mL), using 100:100:1
EtOAc-hexane-Et3N, to afford
2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (2.24
g). Step 4: In a 250-mL flask, the
2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (2.24 g,
5.01 mmol) was dissolved in THF (30 mL). Benzoyl isothiocyanate (0.607
mL, 4.51 mmol) was added. After 1 h, the mixture was concentrated. The
residue was taken up in ACN (30 mL), and catalytic TEA (0.069 mL, 0.501
mmol) was added, followed by DCC (1.137 g, 5.51 mmol). A water-cooled
condenser was affixed, and the solution was stirred in an 80° C.
oil bath for 2 h. The reaction was then concentrated. The residue was
used directly in the next step without further purification. Step 5: In a
150-mL resealable vessel, the crude
N-(3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]ox-
azine]-2'-yl)benzamide from the above procedure was dissolved in 1:1
THF-MeOH (12 mL). Aqueous NaOH (12.04 mL, 30.1 mmol) was added. The
vessel was sealed and heated in a 90° C. oil bath. After 2 h, the
reaction was concentrated to remove most of the THF and MeOH. The aqueous
residue was diluted with water (35 mL), and the aqueous layer was
extracted with 5% MeOH-dcm (3×100 mL). The organics were combined,
washed with dilute brine (35 mL), dried over sodium sulfate and
concentrated. The residue was purified through silica gel (300 mL) using
3% MeOH-dcm, to afford intermediate 25
(3-bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxaz-
in]-2'-amine) (1.99 g). MS (m/z) 472/474 (M+H).sup.+.

[0526] Step 1: In a 350-mL resealable vessel the
(S)-2'-bromo-7'-iodo-5H-spiro[oxazole-4,9'-xanthen]-2-amine (11.5 g, 25.2
mmol) was taken up in AcOH (125 mL) and water (31 mL). The vessel was
sealed and heated in a 140° C. oil bath for 14 h. The reaction was
concentrated to remove most of the AcOH. The reaction residue was
neutralized with 1M aqueous Na2CO3 (250 mL). The residue was
filtered through Celite, rinsing with 5% MeOH-DCM (800 mL). The
filtrate's organic layer was separated, dried over sodium sulfate and
concentrated. The crude
(S)-2'-bromo-7'-iodospiro[oxazolidine-4,9'-xanthen]-2-one was used in the
next step without further purification. Step 2: In a 350-mL resealable
vessel, the (S)-2'-bromo-7'-iodospiro[oxazolidine-4,9'-xanthen]-2-one (11
g, 24.02 mmol) was dissolved in 1:1 MeOH-dioxane (160 mL). Aqueous KOH (5
M, 48.0 mL, 240 mmol) was added. The vessel was sealed and placed in a
105° C. oil bath. After 24 h, the reaction was concentrated to
remove the MeOH and most of the dioxane. The residue was diluted with
water (200 mL) and the aqueous phase was extracted with 5% MeOH-DCM
(4×200 mL). The organics were combined, washed with dilute brine
(35 mL), dried over sodium sulfate and concentrated. The residue was
purified by chromatography (1.5% MeOH/DCM) to afford
(S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g, 8.89 mmol).
Step 3: The (S)-(9-amino-2-bromo-7-iodo-9H-xanthen-9-yl)methanol (3.84 g,
8.89 mmol) was dissolved in THF (200 mL). The solution was cooled to
0° C., and TEA (1.425 mL, 10.22 mmol) and 2-chloroacetyl chloride
(0.707 mL, 9.07 mmol) were added. The reaction was allowed to warm
naturally to RT. After 14 h, the reaction was concentrated. The residue
was taken up in aqueous 1 M Na2CO3 (50 mL) and the aqueous
phase was extracted with 7.5% MeOH-DCM (3×133 mL). The organics
were combined, washed with aqueous 1 M Na2CO3 (30 mL), dried
over sodium sulfate and concentrated. The residue was dissolved in THF
(100 mL) and aqueous 1 M Na2CO3 (15 mL) was added. The reaction
was concentrated. The residue was taken up in 5% MeOH-dcm (400 mL) and
the organic phase was washed with dilute brine (40 mL), dried over sodium
sulfate concentrated to afford crude
(S)--N-(2-bromo-9-(hydroxymethyl)-7-iodo-9H-xanthen-9-yl)-2-chloroacetami-
de, which was used in the next step without further purification. Step 4:
In a 500-mL
flask(S)--N-(2-bromo-9-(hydroxymethyl)-7-iodo-9H-xanthen-9-yl)-2-chloroac-
etamide (4.52 g, 8.89 mmol) was dissolved in t-amyl alcohol (125 mL).
Potassium t-butoxide (2.244 g, 20.00 mmol) was added. After 14 h, the
reaction was concentrated. The residue was taken up in dilute aqueous
NH4Cl (50 mL) and the aqueous phase was extracted with 5% MeOH-DCM
(3×133 mL). The organics were combined, washed with dilute brine
(25 mL), dried over sodium sulfate and concentrated. The material was
purified through silica gel (500 mL) using 30% EtOAc-hexane to afford
(S)-2'-bromo-7'-iodospiro[morpholine-3,9'-xanthen]-5-one (1.92 g, 4.07
mmol). Step 5: In a 250-mL flask, the
(S)-2'-bromo-7'-iodospiro[morpholine-3,9'-xanthen]-5-one (1.483 g, 3.14
mmol) was suspended in toluene (30 mL). Lawesson's reagent (0.794 g,
1.963 mmol) was added. An air-cooled condenser was affixed, and the
reaction vessel was placed in a 90° C. oil bath. After 7 h, the
reaction was concentrated. Without working it up, the residue was
purified by chromatography (15% EtOAc/hexanes) to afford
(S)-2'-bromo-7'-iodospiro[morpholine-3,9'-xanthene]-5-thione (1.25 g,
2.56 mmol). Step 6: In a 350-mL resealable vessel, the
(S)-2'-bromo-7'-iodospiro[morpholine-3,9'-xanthene]-5-thione (1.25 g,
2.56 mmol) was dissolved in a dioxane solution of ammonia (0.5 M, 61.5
mL, 30.7 mmol). After the solid had dissolved, mercury(II) chloride
(1.043 g, 3.84 mmol) was added. The vessel was sealed and placed in a
55° C. oil bath overnight. The reaction was filtered through
Celite, rinsing with DCM (50 mL). The mixture was concentrated to remove
the DCM, and Boc2O (0.84 g, 3.84 mmol) and Et3N (0.535 mL, 3.84
mmol) were added. After 1.5 h, the mixture was concentrated, and the
residue was purified by chromatography (15% EtOAc/hexanes) to afford
impure (S)-tert-butyl
2'-bromo-7'-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-5-ylcarbama-
te. Step 7: In a 150-mL resealable vessel, the (S)-tert-butyl
2'-bromo-7'-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-5-ylcarbama-
te (1.475 g, 2.58 mmol) was dissolved in dcm (10 mL), and
2,2,2-trifluoroacetic acid (1.989 mL, 25.8 mmol) was added. The vessel
was sealed and placed in a 50° C. oil bath. After 2 h, the
reaction was concentrated and the mixture was neutralized with 0.5 M
aqueous Na2CO3 (15 mL) and the aqueous phase was extracted with
5% MeOH-dcm (3×33 mL). The organics were combined, washed with
dilute brine (10 mL), dried over sodium sulfate and concentrated. The
residue was purified by chromatography (5.5% MeOH/DCM) to afford
(S)-2'-bromo-7'-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine
(151 mg, 0.321 mmol). MS (m/z) 471/473 (M+H).sup.+.

Example 28

##STR00047##

[0527] Synthesis of Intermediates 28 and 29

[0528] Step 1: The same reagents and reaction conditions in Steps 1-4 of
Procedure ZZ were used to convert
(S)-2'-bromo-4'-fluoro-7'-methoxy-5H-spiro[oxazole-4,9'-xanthen]-2-amine
to (S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one.
MS (m/z) 394/396 (M+H).sup.+. Step 2: The same reagents and reaction
conditions in Steps 5-7 of Procedure ZZ were used to convert
(S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one to
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine. MS (m/z) 393/395 (M+H)'.

Example 29

##STR00048##

[0529] Synthesis of Intermediates 30 and 31

[0530] Step 1: The same reagents and conditions in Steps 1-4 in Procedure
ZZ were used to convert
(S)-2'-bromo-7'-methoxy-5H-spiro[oxazole-4,9'-xanthen]-2-amine to
(S)-2'-bromo-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one. Step 2: The
same reagents and conditions in Steps 5-7 of Procedure ZZ were used to
convert (S)-2'-bromo-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one to
(S)-2'-bromo-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-ami-
ne. MS (m/z) 375/377 (M+H).sup.+.

[0537] Step 1: A vial was charged with
(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4-
]oxazin]-5'-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic
acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(50.8 mg, 0.072 mmol). The vial was flushed with Ar (g), then dioxane
(5383 μL) and water (1794 μL) were added in sequence. The vial was
sealed and heated in a Biotage Initiator microwave reactor for 20 min at
90° C. The mixture was diluted with water and extracted with EtOAc
(3×). The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated. The residue was purified by chromatography
(0-100% EtOAc/Hexane) to give
(S)-3-chloro-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-c]p-
yridine-5,3'-[1,4]oxazin]-5'-amine (510.4 mg, 95% purity) as an off-white
solid. Step 2: A vial was charged with
(S)-3-chloro-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-c]p-
yridine-5,3'-[1,4]oxazin]-5'-amine (60.4 mg, 0.152 mmol),
4,4-difluoropiperidine hydrochloride (27.7 mg, 0.228 mmol), and X-Phos
Precatalyst (25.2 mg, 0.030 mmol). The vial was flushed with Ar (g), then
capped with a septum. Lithium bis(trimethylsilyl)amide (1M in THF) (533
μL, 0.533 mmol) was added in one portion at rt. After 30 min. the
reaction mixture was diluted with saturated aq. ammonium chloride
solution and extracted with EtOAc (3×). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated. The
residue was purified by chromatography (30% of a 90:10:1 mixture of
DCM/MeOH/NH4OH in DCM) to give 43 mg of an oil. The oil was further
purified by reverse-phase HPLC (15-90% CH3CN/H2O with 0.1%
TFA). Fractions containing product were combined and washed with
saturated aq. sodium bicarbonate solution. The mixture was extracted with
DCM (3×). The combined organic extracts were dried over sodium
sulfate, and concentrated to give
(S)-3-(4,4-difluoropiperidin-1-yl)-7-(2-fluoropyridin-3-yl)-2',6'-dihydro-
spiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine as a white solid.
MS m/z=482.1 [M+H].sup.+.

[0540] Step 1: A vial was charged with 2,2-dimethylpropan-1-ol (100 mg,
1.130 mmol) and DMSO (1130 μL). Sodium hydride (60% in mineral oil;
45.2 mg, 1.130 mmol) was added. The vial was placed in a 100° C.
oil bath for 5 min. the reaction mixture was cooled to room temperature
and (S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'--
[1,4]oxazin]-5'-amine (86 mg, 0.226 mmol) was added in one portion. The
vial was sealed and heated in a 100° C. oil bath for 2 h. The
mixture was cooled to room temperature, then diluted with water and
EtOAc. Brine was added, and the layers were separated. The aq. layer was
extracted with EtOAc (2×). The combined organic extracts were dried
over sodium sulfate, and concentrated. The residue was purified by
chromatography (0-100% EtOAc/Hexane) to give
(S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5-
,3'-[1,4]oxazin]-5'-amine as a light-yellow solid. Step 2: A vial was
charged with
(S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5-
,3'-[1,4]oxazin]-5'-amine (51 mg, 0.118 mmol), 2-fluoropyridin-3-ylboronic
acid (33.2 mg, 0.236 mmol), potassium phosphate (75 mg, 0.354 mmol), and
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(4.18 mg, 5.90 μmol). The vial was flushed with Ar (g), then dioxane
(442 μL) and water (147 μL) were added in sequence. The vial was
sealed and heated in a Biotage Initiator microwave reactor for 20 min at
90° C. The mixture was extracted with EtOAc (3×), and the
combined organic extracts were concentrated. The residue was purified by
chromatography (30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM)
to give (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro[-
chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (46.23 mg) as an
off-white solid. MS m/z=449.2 [M+H].sup.+.

[0543] Step 1: A vial was charged with
(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4-
]oxazin]-5'-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic
acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(50.8 mg, 0.072 mmol). The vial was flushed with Ar (g), then dioxane
(5383 μL) and water (1794 μL) were added in sequence. The vial was
sealed and heated in a Biotage Initiator microwave reactor for 20 min at
90° C. The mixture was diluted with water and extracted with EtOAc
(3×). The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated. The residue was purified by chromatography on
silica gel (0-100% EtOAc/Hexane) to give
(S)-3-chloro-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-c]p-
yridine-5,3'-[1,4]oxazin]-5'-amine (510.4 mg) as an off-white solid
containing ca. 5% of the bis-coupled byproduct. Step: A vial was charged
with and (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromen-
o[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (79.05 mg, 0.199 mmol),
3,6-dihydro-2H-pyran-4-ylboronic acid (76 mg, 0.598 mmol),
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(7.05 mg, 9.96 μmol), and potassium phosphate (127 mg, 0.598 mmol).
Dioxane (747 μL) and water (249 μL) were added, and the vial was
sealed and heated in a Biotage Initiator microwave reactor for 30 min at
110° C. The mixture was extracted with EtOAc (3×), and the
combined organic extracts were concentrated. The residue was purified by
chromatography on silica gel (0-10% MeOH/DCM) to give
(S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2',6'-dihydros-
piro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (82.18 mg) as a
yellow solid. Step: A 10-mL round-bottom flask was charged with
(S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-2',6'-dihydros-
piro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (82.8 mg, 0.186
mmol) and MeOH (2.5 mL). The flask was flushed with Ar (g), then 10% Pd/C
(ca. 35 mg) was added. H2 (g) was bubbled through the mixture for 1
min, then the reaction mixture was stirred under an H2 (g)
atmosphere overnight. An additional portion of 10% Pd/C (21 mg) was
added, and H2 (g) was bubbled through for 1 min. After stirring
overnight, the mixture was filtered through celite, and the filter cake
was washed with methanol. The filtrate was concentrated, and the residue
was purified by chromatography (10-40% of a 90:10:1 mixture of
DCM/MeOH/NH4OH in DCM) to give
(S)-7-(2-fluoropyridin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)-2',6'-dihydrosp-
iro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (72 mg) as an
off-white solid. [M+H]+=447.2.

[0545] Step 1: A 250 ml RBF was charged with
7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-
-5-amine (2.73 g, 6.94 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(0.492 g, 0.694 mmol) and 2-fluoropyridin-3-ylboronic acid (1.467 g,
10.41 mmol). Dioxane (40 mL) and potassium carbonate (1M in water; 20.83
mL, 20.83 mmol) were added and the mixture was flushed with argon and
heated at 85° C. for 30 minutes. The mixture was cooled to RT,
diluted with EtOAc and the organic layer was separated and concentrated
in vacuo to give a yellow residue. After triturating with 10 ml of
ethanol the solid was filtered off, washed with EtOH (2×1 ml) and
dried on air overnight to afford
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-methoxy-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-5-amine (2.11 g, 5.15 mmol).

Step 2: To a suspension of
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-methoxy-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-5-amine (1.668 g, 4.07 mmol) in DCM (12 ml) was added
boron tribromide (0.963 mL, 10.19 mmol) at 0° C. The reaction
mixture was stirred for 45 hrs at 0° C. The reaction mixture was
allowed to warm to RT and was stirred for additional 2 hrs. The reaction
mixture was cooled to 0° C. and quenched by addition of saturated
aqueous NaHCO3 solution (˜10 mL). The solvent was removed in
vacuo, the mixture was diluted with water and filtered. The solid was
washed with water and dried under reduced pressure to afford
5-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthen]-2'-ol (1.53 g, 3.87 mmol, 95% yield). Step 3: To a
suspension of
5-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthen]-2'-ol (1.01 g, 2.55 mmol) in DCM (12.77 mL) were added TEA
(1.424 mL, 10.22 mmol) and
N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)metha-
nesulfonamide (1.103 g, 2.81 mmol). After stirring for 2 hours the
reaction mixture was washed 3× with 2N NaOH solution followed by
brine. The solution was then concentrated. The yellow residue was diluted
with DCM (5 ml) and the white precipitate was filtered, washed with DCM
and dried under a stream of air to afford 355 mg (26%) of pure product.
The filtrate was purified by chromatography (5-40% DCM/MeOH/NH4OH in
DCM) to afford
5-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthene]-7'-yl trifluoromethanesulfonate (880 mg, 1.668 mmol, 65.3%
yield) as a white foam. Total isolated
5-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthene]-7'-yl trifluoromethanesulfonate (1235 mg, 2.342 mmol, 92%
yield). Step 4: A re-sealable vial was charged with
5-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthene]-7'-yltrifluoromethanesulfonate (200 mg, 0.379 mmol),
chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2-am-
inoethylphenyl)]palladium(II) 1 (27.6 mg, 0.038 mmol) and 0.5 ml of THF.
The mixture was stirred at RT until all solids were dissolved. Morpholine
(66.1 μL, 0.758 mmol) and LiHMDS (1M in THF) (1138 pt, 1.138 mmol)
were added and the vial was sealed and stirred at RT for 20 minutes. The
reaction was quenched by addition of water (1 ml) and diluted with EtOAc
(2 ml). The organic layer was separated, and the aqueous layer was
extracted with EtOAc (2×2 ml). The combined organic fractions were
concentrated and purified by chromatography (10-80% DCM/MeOH/NH4OH
in DCM) to provide racemic
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-morpholino-2,6-dihydrospiro[[1,4]o-
xazine-3,9'-xanthen]-5-amine (97 mg, 0.209 mmol, 55.1% yield). Step 5: The
final compound
(S)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-morpholino-2,6-dihydrospiro[[1-
,4]oxazine-3,9'-xanthen]-5-amine was obtained from racemic
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-morpholino-2,6-dihydrospiro[[1,4]o-
xazine-3,9'-xanthen]-5-amine using similar chiral separation conditions as
described herein for intermediate 10.

[0547] Step 1: A 250 ml RBF was charged with
7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-
-5-amine (2.73 g, 6.94 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(0.492 g, 0.694 mmol) and 2-fluoropyridin-3-ylboronic acid (1.467 g,
10.41 mmol). Dioxane (40 mL) and potassium carbonate (1M solution) (20.83
mL, 20.83 mmol) were added and the mixture was flushed with argon and
heated at 85° C. for 30 minutes. The mixture was cooled to RT,
diluted with EtOAc and the organic layer was separated and concentrated
in vacuo to give a yellow semisolid. After trituration with 10 ml of EtOH
the solid was filtered, washed with EtOH (2×1 ml) and dried on air
overnight to afford
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-methoxy-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-5-amine (2.11 g, 5.15 mmol). Step: To a suspension of
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-methoxy-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-5-amine (1.668 g, 4.07 mmol) in DCM (12 ml) was added
boron tribromide (0.963 mL, 10.19 mmol). Stirring was continued for 45
hrs at 0° C. at which point the mixture was removed from the bath
and stirred for 2 hrs at RT. The reaction mixture was recooled to
0° C. and quenched by careful addition of saturated aqueous
NaHCO3 solution (˜10 mL). The mixture became colorless with a
white precipitate. The solvent was removed in vacuo, the mixture was
diluted with water and filtered. The solid was washed with water and
dried on air for 2 hrs, then for 2 hrs in high vacuum at RT to afford
5-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthen]-2'-ol (1.53 g, 3.87 mmol, 95% yield). Step 3: To a
suspension of
5-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthen]-2'-ol (1.01 g, 2.55 mmol) in DCM (12.77 mL) were added TEA
(1.424 mL, 10.22 mmol) and
N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)metha-
nesulfonamide (1.103 g, 2.81 mmol). After stirring for 2 hours the
reaction mixture was washed 3× with 2N NaOH solution followed by
brine. The solution was then concentrated. The yellow residue was diluted
with DCM (5 ml) and the white precipitate was filtered, washed with DCM
and dried under a stream of air to afford 355 mg (26%) of pure product.
The filtrate was purified by chromatography (5-40% DCM/MeOH/NH4OH in DCM)
to afford 5-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1-
,4]oxazine-3,9'-xanthene]-7'-yltrifluoromethanesulfonate (880 mg, 1.668
mmol, 65.3% yield) as a white foam. Total isolated
5-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthene]-7'-yl trifluoromethanesulfonate (1235 mg, 2.342 mmol, 92%
yield). Step 4: A 10 ml resealable tube was charged with
5-amino-5'-fluoro-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthene]-7'-yltrifluoromethanesulfonate (385 mg, 0.730 mmol),
2-fluoropyridin-4-ylboronic acid (165 mg, 1.168 mmol),
PdCl2(dppf)-DCM adduct (59.6 mg, 0.073 mmol), dioxane (3650 pt) and
potassium carbonate (1M solution) (2190 μL, 2.190 mmol). The mixture
was flushed with argon, sealed and heated at 85° C. for 1 hr. The
mixture was diluted with EtOAc, organic layer was filtered through Celite
and concentrated. The brown residue was purified by chromatography
(10-80% DCM/MeOH/NH4OH in DCM) to afford
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-(2-fluoropyridin-4-yl)-2,6-dihydro-
spiro[[1,4]oxazine-3,9'-xanthen]-5-amine (294 mg, 85% yield) as off-white
solid. Step 5: The final compound
(S)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-(2-fluoropyridin-4-yl)-2,6-dih-
ydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine (36A) were obtained form
racemic 4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-(2-fluoropyridin-4-yl)-2,6-
-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine using similar chiral
separation conditions as described herein for intermediate 10.

[0551] Step 1: A 250 ml RB flask was charged with
7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-
-5-amine (2.73 g, 6.94 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(0.492 g, 0.694 mmol) and 2-fluoropyridin-3-ylboronic acid (1.467 g,
10.41 mmol). Dioxane (40 mL) and potassium carbonate (1M solution) (20.83
mL, 20.83 mmol) were added and the mixture was flushed with argon and
heated at 85° C. for 30 minutes. The mixture was cooled to RT,
diluted with EtOAc and the organic layer was separated and concentrated
in vacuo to give a yellow semisolid. After trituration with 10 ml of EtOH
the solid was filtered, washed with EtOH (2×1 ml) and dried on air
overnight to afford
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-methoxy-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-5-amine (2.11 g, 5.15 mmol). Step 2: To a suspension of
4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-methoxy-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-5-amine (1.668 g, 4.07 mmol) in DCM (12 ml) was added
boron tribromide (0.963 mL, 10.19 mmol). Stirring was continued for 45
hrs at 0° C. at which point the mixture was removed from the bath
and stirred for 2 hrs at RT. The reaction mixture was recooled to
0° C. and quenched by careful addition of saturated aqueous
NaHCO3 solution (˜10 mL). The mixture became colorless with a
white precipitate. The solvent was removed in vacuo, the mixture was
diluted with water and filtered. The solid was washed with water and
dried on air for 2 hrs, then for 2 hrs in high vacuum at RT to afford
5-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-
-3,9'-xanthen]-2'-ol (1.53 g, 3.87 mmol, 95% yield). Step 3: To a solution
of 5-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxaz-
ine-3,9'-xanthen]-2'-ol (200 mg, 0.506 mmol) in DMF (2529 μL) cesium
carbonate (330 mg, 1.012 mmol), KI (25.2 mg, 0.152 mmol) and
2-fluoro-2-methylpropyl trifluoromethanesulfonate (125 mg, 0.556 mmol)
were added sequentially and the resulting mixture was stirred overnight
at RT. The mixture was diluted with 5 ml of water and stirred for 5
minutes. The solvents were decanted from a precipitated gummy solid. 10
ml of water was added and the mixture was stirred for 1 hr at RT at which
point a fine precipitate formed. The solids were filtered, washed with
water and dried on air for 3 hr, then overnight in vacuo to afford
racemic 4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-
-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine (175 mg, 73% yield).
Step 4: The final compound
(S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-2,6-
-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine (37A) was obtained form
racemic 4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-
-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine using similar chiral
separation conditions as described herein for intermediate 10.

[0557] Step 1: In a 500-mL flask,
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (0.676 g, 1.719 mmol) was suspended in DCM (50 mL). The
suspension was cooled to 0° C., and boron tribromide (1.0 M in
DCM; 5.16 mL, 5.16 mmol) was added. After 1.5 h, excess boron tribromide
was quenched with saturated aqueous NH4Cl (18 mL) and aqueous
NH4OH (2 mL). The aqueous phase was separated and extracted further
with 5% MeOH-DCM (3×50 mL). The organics were combined, washed with
brine (15 mL), dried over sodium sulfate and concentrated to afford 604
mg of (S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-x-
anthen]-7'-ol which was used in the next step without further
purification. Step 2: A flask was charged with
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol (10 mg, 0.026 mmol) and dioxane (0.6 mL).

[0558] Triethylamine (10.5 μL, 0.076 mmol) and di-tert-butyl
dicarbonate (0.017 g, 0.076 mmol) were added, and the solution was
stirred at RT for 14 h. The material was taken up in 1 M aqueous HCl (10
mL) and the aqueous phase was extracted with DCM (3×20 mL). The
organics were combined, dried over sodium sulfate and concentrated. The
material was purified by chromatography (30% ethyl acetate/hexane) to
afford 12 mg of (5)-tert-butyl
2'-bromo-4'-fluoro-7'-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene-
]-5-ylcarbamate.

Step 3: A microwave vial was charged with potassium acetate (6.14 mg,
0.063 mmol),
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(1.77 mg, 2.504 μmol), and 2-fluoropyridin-4-ylboronic acid (4.23 mg,
0.030 mmol). The (S)-tert-butyl
2'-bromo-4'-fluoro-7'-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene-
]-5-ylcarbamate (0.012 g, 0.025 mmol) was added as a solution in 1:1
acetonitrile/dioxane (1 mL). Water (0.1 mL) was added. Argon was blown
through the vessel, which was then sealed and heated in a 100° C.
oil bath for 6 h. The mixture was cooled, diluted with brine (10 mL), and
the aqueous layer was extracted with 10% MeOH-DCM (3×20 mL). The
organics were combined, washed with dilute brine (5 mL), dried over
sodium sulfate and concentrated. The residue was purified by preparative
TLC (20% MeOH in DCM) to afford 3.8 mg of
(S)-5-amino-4'-fluoro-2'-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxa-
zine-3,9'-xanthen]-7'-ol.

[0560] Step 1: In a 250-mL flask, Lawesson's reagent (0.577 g, 1.427 mmol)
and (S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one
(0.978 g, 2.481 mmol) were suspended in toluene (25 mL). An air-cooled
condenser was attached, and the flask was heated in a 90° C. oil
bath for 3 h. The mixture was then cooled and concentrated to give
(S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthene]-5-thione
which was used in the next step without further purification.

Step 2: In a 150-mL resealable vessel, the crude
(S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthene]-5-thione
(1.0 g, 2.437 mmol) was dissolved in a dioxane solution of ammonia (0.5
M, 58.5 mL, 29.2 mmol). Mercury (II) chloride (0.993 g, 3.66 mmol) was
added, and the vessel was sealed and heated in a 55° C. oil bath
overnight. The mixture was then cooled and concentrated. The residue was
filtered through Celite, rinsing with 10% MeOH-DCM (400 mL). The filtrate
was concentrated, and the residue was purified through silica gel (150
mL) using 7.5% MeOH-DCM to afford 131 mg of
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine Step 3: In a 100-mL flask,
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (0.233 g, 0.593 mmol) was dissolved in DCM (7.5 mL). The
solution was cooled to 0° C., and a DCM solution of boron
tribromide (1 M, 1.78 mL, 1.78 mmol) was added. The mixture was stirred
at 0° C. for 1 h, then was quenched with saturated aqueous
NH4Cl (18 mL) and aqueous NH4OH (2 mL). The aqueous phase was
extracted 5% MeOH-DCM (3×40 mL). The organics were combined, washed
with dilute brine (15 mL), dried over sodium sulfate and concentrated to
afford 187 mg of
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol. Step 4: In a microwave vial, potassium phosphate (0.307 g, 1.448
mmol), PdCl2(AmPhos)2 (0.026 g, 0.036 mmol),
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol (0.183 g, 0.483 mmol), and
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.147 g, 0.700 mmol) were suspended in dioxane (4 mL) and water (1.6
mL). Argon was blown through the vessel, which was sealed and heated by
microwave at 120° C. for 30 min. The reaction was concentrated,
and the residue was neutralized with 1/3 saturated aqueous NH4Cl (15
mL) and the aqueous phase was extracted with 5% MeOH-DCM (3×25 mL).
The organics were combined, washed with dilute brine (7 mL), and
concentrated to afford
(S)-5-amino-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-2,6-dihydrospiro[[1,-
4]oxazine-3,9'-xanthen]-7'-ol which was used in the next step without
further purification. Step: In a 100-mL flask, the crude
(S)-5-amino-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-2,6-dihydrospiro[[1,-
4]oxazine-3,9'-xanthen]-7'-ol (0.185 g, 0.484 mmol) was suspended in THF
(12 mL). Boc2O (0.132 g, 0.605 mmol) was added, followed by TEA
(0.088 mL, 0.629 mmol). The mixture was stirred at rt overnight. The
mixture was concentrated to afford (5)-tert-butyl
2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-7'-hydroxy-2,6-dihydrospiro[[1,4-
]oxazine-3,9'-xanthene]-5-ylcarbamate which was used in the next step
without further purification. Step 6: In a 100-mL flask, the crude
(5)-tert-butyl
2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-7'-hydroxy-2,6-dihydrospiro[[1,4-
]oxazine-3,9'-xanthene]-5-ylcarbamate (0.233 g, 0.483 mmol) was dissolved
in DCM (10 mL). The solution was cooled to 0° C., and TEA (0.157
mL, 1.14 mmol) was added, followed by
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
(0.362 g, 1.01 mmol). After 2 h, the reaction was quenched with aqueous
sodium bicarbonate (5 mL). The mixture was diluted with water (10 mL) and
the aqueous phase was extracted with 3% MeOH-DCM (3×20 mL). The
organics were combined, washed with dilute brine (7 mL), dried over
sodium sulfate and concentrated. The residue was purified through silica
gel (50 mL) using 30% EtOAc in hexane to afford 166 mg of
(S)-5-(tert-butoxycarbonylamino)-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-
-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7'-yl
trifluoromethanesulfonate. Step 7: In a microwave vial,
2-fluoropyridin-3-ylboronic acid (0.048 g, 0.338 mmol),
(S)-5-(tert-butoxycarbonylamino)-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-
-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7'-yltrifluoromethanesulfona-
te (0.166 g, 0.270 mmol), and Pd(PPh3)4 (0.031 g, 0.027 mmol)
were suspended in DMF (3 mL). Aqueous sodium carbonate (1 M, 0.810 mL,
0.810 mmol) was added. Argon was blown through the vessel, which was
sealed and heated in an 85° C. oil bath for 2.5 h. The reaction
was cooled and concentrated. The residue was taken up in water (15 mL)
and the aqueous phase was extracted with 3% MeOH-DCM (3×25 mL). The
organics were combined, washed with dilute brine (7 mL), dried over
sodium sulfate and concentrated. The residue was transferred to a
microwave vial in DCM (3 mL), and TFA (0.520 mL, 6.75 mmol) was added.
The vial was sealed and heated in a 65° C. oil bath for 1.5 h. The
mixture was cooled and concentrated, and the residue was neutralized with
0.5 M aqueous Na2CO3 (15 mL) and the aqueous phase was
extracted with 5% MeOH-DCM (3×25 mL). The organics were combined,
washed with dilute brine (7 mL), dried over sodium sulfate and
concentrated. The residue was purified through silica gel (50 mL) using
8% MeOH-DCM to afford 72 mg of
(S)-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,-
6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine. m/z=462.0[M+H].sup.+.

[0563] Step 1: In a 1-L flask, the
(S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one
(3.16 g, 8.02 mmol) was suspended in toluene (75 mL). Lawesson's reagent
(1.864 g, 4.61 mmol) was added. An air-cooled condenser was affixed, and
the mixture was heated in a 90° C. oil bath for 2 h. The mixture
was cooled and concentrated to afford crude
(S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthene]-5-thione
which was used in the next step without further purification. Step 2: In
a 350-mL resealable vessel, the
(S)-2'-bromo-4'-fluoro-7'-methoxyspiro[morpholine-3,9'-xanthene]-5-thione
(3.0 g, 7.31 mmol) was dissolved in a dioxane solution of ammonia (0.5 M,
175 mL, 88 mmol). Mercury (II) chloride (2.98 g, 10.97 mmol) was added,
and the vessel was sealed and heated in a 55° C. oil bath
overnight. The reaction was cooled and then filtered through Celite,
rinsing with 10% MeOH-DCM. The filtrate was concentrated, and the residue
was transferred to a resealable vessel with 50 mL of dioxane. A solution
of ammonia in dioxane (0.5 M, 100 mL, 50 mmol) was added, followed by
mercury (II) chloride (2.0 g, 7.36 mmol). The vessel was sealed and
heated in a 60° C. oil bath for 14 h. The mixture was cooled and
filtered through Celite, rinsing with 10% MeOH-DCM. The filtrate was
concentrated, and the residue was purified through silica gel (300 mL)
using 7.5% MeOH-DCM to afford 1.33 g of
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine Step 3: In a 50-mL flask, the
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (0.340 g, 0.864 mmol) was taken up in DCM (15 mL). The
suspension was cooled to 0° C., and a DCM solution of boron
tribromide (2.59 mL, 2.59 mmol) was added. After 1 h, the reaction was
quenched with 18 mL of saturated aqueous NH4Cl and 2 mL of aqueous
NH4OH. The mixture was diluted further with water (10 mL), and the
aqueous phase was extracted with 5% MeOH-DCM (3×50 mL). The
organics were combined, washed with dilute brine (15 mL), dried over
sodium sulfate and concentrated to afford 241 mg of
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol which was used in the next step without further purification. Step
4: A microwave vial was charged with tetrabutylammonium fluoride
trihydrate (0.301 g, 0.952 mmol), Pd(PPh3)4 (0.073 g, 0.063
mmol), and copper(I) iodide (12.3 mg, 0.065 mmol). The
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol (0.241 g, 0.64 mmol) was added as a solution in THF (2.7 mL).
Argon was blown through the vessel, and
trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.161 g, 0.951 mmol) was
added. The vessel was sealed and heated in an 80° C. oil bath for
1.5 h. The mixture was cooled and concentrated, diluted with water (15
mL), and the aqueous phase was extracted with 5% MeOH-DCM (3×25
mL). The organics were combined, washed with dilute brine (7 mL), dried
over sodium sulfate and concentrated to afford
(S)-5-amino-4'-fluoro-2'4(3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[-
1,4]oxazine-3,9'-xanthen]-7'-ol, which was used in the next step without
further purification. Step: In a 50-mL flask, the crude
(S)-5-amino-4'-fluoro-2'4(3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[-
1,4]oxazine-3,9'-xanthen]-7'-ol (0.251 g, 0.636 mmol) was dissolved in THF
(12 mL). Boc2O (0.303 g, 1.39 mmol) and triethylamine (0.204 mL,
1.47 mmol) were added. After 14 h, the reaction mixture was concentrated
to afford (S)-tert-butyl
4'-fluoro-7'-hydroxy-2'4(3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1-
,4]oxazine-3,9'-xanthene]-5-ylcarbamate which was used in the next step
without further purification. Step 6: In a 50-mL flask, the crude
(5)-tert-butyl
4'-fluoro-7'-hydroxy-2'43-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,-
4]oxazine-3,9'-xanthene]-5-ylcarbamate (0.315 g, 0.637 mmol) was dissolved
in DCM (12 mL). The solution was cooled to 0° C., and
triethylamine (0.175 mL, 1.26 mmol) and
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
(0.400 g, 1.12 mmol) were added. After 2.5 h, the reaction was quenched
with dilute aqueous NaHCO3 (15 mL) and the aqueous phase was
extracted with 3% MeOH-DCM (3×20 mL). The organics were combined,
dried over sodium sulfate and concentrated. The residue was purified
through silica gel (60 mL) using 25% ethyl acetate in hexane to afford
230 mg of (S)-5-(tert-butoxycarbonylamino)-4'-fluoro-2'43-methyloxetan-3--
yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7-yl
trifluoromethanesulfonate Step 7: In a microwave vial,
2-fluoropyridin-3-ylboronic acid (0.065 g, 0.459 mmol),
Pd(PPh3)4 (0.042 g, 0.037 mmol) and
(S)-5-(tert-butoxycarbonylamino)-4'-fluoro-2'4(3-methyloxetan-3-yl)ethyny-
l)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7'-yl
trifluoromethanesulfonate (0.230 g, 0.367 mmol) were taken up in DMF (3
mL). Aqueous sodium carbonate (1.0 M, 1.10 mL, 1.10 mmol) was added.
Argon was blown through the vessel which was then sealed and heated in an
85° C. oil bath for 4 h. The reaction was cooled and concentrated,
and the residue was diluted with water (15 mL) and the aqueous phase was
extracted with 3% MeOH-DCM (3×25 mL). The organics were combined,
washed with dilute brine (7 mL), dried over sodium sulfate and
concentrated. The residue was purified through silica gel (33 mL) which
had been deactivated with Et3N (3.3 mL), using 33% EtOAc in hexane.
The resulting residue was transferred to a microwave vessel in DCM (3
mL), and TFA (0.283 mL, 3.67 mmol) was added. The vessel was sealed and
heated in a 60° C. oil bath for 1.5 h. The reaction was cooled and
concentrated, and the residue was neutralized with 0.5 M aqueous
Na2CO3 (15 mL). The aqueous phase was extracted with 5%
MeOH-DCM (3×25 mL). The organics were combined, washed with dilute
brine (7 mL) and dried over sodium sulfate. The residue was purified
through silica gel (33 mL) using 7.5% MeOH-DCM to afford 27 mg of
(S)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'4(3-methyloxetan-3-yl)ethynyl)--
2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine. m/z=474.0[M+H].sup.+.

[0566] In a microwave vial,
(S)-2'-(3,6-dihydro-2H-pyran-4-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,-
6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine (0.040 g, 0.087 mmol)
and Pd/C (10%, 0.055 g, 0.052 mmol) were suspended in EtOH (1.5 mL). A
balloon full of hydrogen (˜1 L) was emptied into the vessel,
venting through a needle, and the vessel was sealed. After 2 days, the
mixture was filtered through Celite, rinsing with 5% MeOH-DCM. The
filtrate was concentrated, and the residue was purified by chromatography
(7.5% MeOH/DCM) to afford 29 mg of
(S)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-(tetrahydro-2H-pyran-4-yl)-2,6-
-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine

[0568] Step 1: A vial was charged with neopentyl alcohol (0.579 g, 6.57
mmol) and DMF (6.57 mL). Sodium hydride (60% in mineral oil; 0.263 g,
6.57 mmol) was added and the reaction was stirred for 10 minutes at room
temperature. The vial was heated to 100° C. for 5 min. The vial
was cooled to rt.
(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4-
]oxazin]-5'-amine (0.500 g, 1.314 mmol) was added in one portion. The vial
was sealed and heated to 100° C. three hours. The mixture was
diluted with ethyl acetate and water. A small amount of brine was added
and the layers were separated. The aq. layer was extracted twice with
ethyl acetate. The combined organic extracts were dried over sodium
sulfate, filtered, and concentrated. The residue was purified by
chromatography (0-100% EtOAc/Hexanes) to give 175 mg of
(S)--N-(7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridi-
ne-5,3'-[1,4]oxazine]-5'-yl)formamide as a light yellow solid. Step: A
microwave vial was charged with
(S)--N-(7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridi-
ne-5,3'-[1,4]oxazine]-5'-yl)formamide (0.075 g, 0.163 mmol),
2-fluoropyridin-3-ylboronic acid (0.046 g, 0.326 mmol), potassium
phosphate (0.104 g, 0.489 mmol), and
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(5.77 mg, 8.15 μmol). The vial was flushed with Ar (g), then dioxane
(0.611 mL) and water (0.204 mL) were added in sequence. The vial was
sealed and heated in a Biotage Initiator microwave reactor for 30 min at
100° C. The reaction was diluted with EtOAc and washed with water.
The aqueous layer was extracted with EtOAc, and the combined organic
layers were washed with brine, dried with sodium sulfate, filtered, and
concentrated. The material was purified via column chromatography (0-10%
MeOH:DCM w/1% NH4OH) to afford 32 mg of
(S)--N-(7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro[chro-
meno[2,3-c]pyridine-5,3'-[1,4]oxazine]-5'-yl)formamide as an off-white
solid.

[0570] Step 1: A vial was charged with 2,2-dimethylpropan-1-ol (100 mg,
1.130 mmol) and DMSO (1130 μL) to give a clear solution. Sodium
hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added and the vial
was placed in a 100° C. oil bath for 5 min, then was removed from
the heat and cooled to RT.
(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4-
]oxazin]-5'-amine (Intermediate 1B, 86 mg, 0.226 mmol) was added to give
an orange solution. The vial was sealed and heated in a 100° C.
oil bath for 2 h. The mixture was cooled to room temperature, then
diluted with water and EtOAc. Brine was added and the layers were
seperated. The aq. layer was extracted with EtOAc (2×). The
combined organic extracts were dried over sodium sulfate, filtered, and
concentrated. The residue was purified by chromatography on silica gel
(0-100% EtOAc/Hexane) to give
(S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5-
,3'-[1,4]oxazin]-5'-amine as a light-yellow solid. Step 2: A vial was
charged with
(S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5-
,3'-[1,4]oxazin]-5'-amine (74.0 mg, 0.171 mmol) 4,4-difluoropiperidine
hydrochloride (31.1 mg, 0.257 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-1-propyl-1,1'-biphenyl)[2-(2--
aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (12.02 mg,
0.017 mmol). The vial was flushed with Argon and sealed. Lithium
bis(trimethylsilyl)amide (1M in THF) (599 μL, 0.599 mmol) was added in
one portion. The resulting mixture was sonicated for 1 min, then stirred
for 30 min at rt. The reaction mixture was diluted with saturated aq
ammonium chloride solution and extracted with EtOAc (3×). The
combined organic extracts were dried over sodium sulfate, filtered, and
concentrated. The residue was purified by chromatography (0-10% MeOH/DCM)
to give (S)-7-(4,4-difluoropiperidin-1-yl)-3-(neopentyloxy)-2',6'-dihydro-
spiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine as an off-white
solid. [M+H].sup.+=473.2.

[0575] Step 1: A vial was charged with
(S)-7'-bromo-4'-fluoro-2'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (200 mg, 0.509 mmol),
chloro(2-dicyclohexylphosphino-2',6'-di-1-propoxy-1,1'-biphenyl)[2-(2-ami-
noethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025
mmol), 4,4-difluoropiperidine hydrochloride (160 mg, 1.017 mmol) and 1 ml
of THF. The mixture was cooled to 0° C. and LHMDS (1M in THF)
(2035 μL, 2.035 mmol) was added, and the vial was sealed and stirred
at RT for 2 hr. At this point more
chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-ami-
noethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025
mmol), (18.53 mg, 0.025 mmol) was added followed by LHMDS solution (1 ml)
and stirring continued for another hour. The mixture was quenched by
addition of 2 ml of water and extracted with EtOAc. The combined organic
fractions were concentrated and purified by chromatography [5-50%
DCM/MeOH/NH4OH (90:10:1)] to afford
(S)-7'-(4,4-difluoropiperidin-1-yl)-4'-fluoro-2'-methoxy-2,6-dihydrospiro-
[[1,4]oxazine-3,9'-xanthen]-5-amine as yellowish foam. Step 2: To a
solution of
(S)-7'-(4,4-difluoropiperidin-1-yl)-4'-fluoro-2'-methoxy-2,6-dihydrospiro-
[[1,4]oxazine-3,9'-xanthen]-5-amine (130 mg, 0.300 mmol) in DCM (3 ml)
boron tribromide (0.085 ml, 0.900 mmol) was added dropwise at room
temperature and the mixture was stirred for 3 hrs at RT. The reaction was
quenched by addition of MeOH (˜1 ml), stirred for 10 min, then
neutralized by addition of 25% NH4OH. The homogeneous mixture was
concentrated in vacuo and extracted with EtOAc. The organic layer was
washed with brine and concentrated in vacuo to give after trituration
with DCM off white solid. The solid was redissolved in 3 ml of DMF,
cesium carbonate (195 mg, 0.600 mmol) and potassium iodide (14.94 mg,
0.090 mmol) were added and then 3-bromomethyll-3-methyloxetane (0.054 ml,
0.330 mmol) was added dropwise. The mixture was stirred at RT for 4 hrs.
The mixture was diluted with water (10 ml) and extracted with EtOAc. The
combined organic layers was washed twice with water, then with brine and
concentrated in vacuo. The residue was purified by chromatography [10-80%
DCM/MeOH/NH4OH (90:10:1) in DCM] to afford
(S)-7'-(4,4-difluoropiperidin-1-yl)-4'-fluoro-2'4(3-methyloxetan-3-yl)met-
hoxy)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine

[0596] Steps 1 and 2: Synthesis of (E)-(2-nitrovinyl)cyclohexane Step 1:
10 M aqueous NaOH (8.31 mL, 83 mmol) was added dropwise via addition
funnel to a solution of nitromethane (4.46 mL, 83 mmol) and
cyclohexanecarboxaldehyde (10 mL, 83 mmol) in EtOH (20 mL) at 0°
C. with vigorous stirring. The resulting white slurry was stirred 10
minutes and became a white solid. Acetic acid (4.76 mL, 83 mmol) was
added and the reaction was partitioned between diethyl ether and water.
The layers were separated and the aqueous layer was extracted with
diethyl ether. The combined organic extracts were washed with water,
saturated aqueous sodium chloride, and dried over magnesium sulfate. The
solution was filtered and concentrated in vacuo and dried under vacumm to
afford 1-cyclohexyl-2-nitroethanol. The product was used directly for the
next step without further purification. Step 2: Methanesulfonyl chloride
(2.83 mL, 36.4 mmol) was added via syringe to a solution of
(E)-(2-nitrovinyl)cyclohexane and hydroquinone (0.200 g, 1.819 mmol) in
DCM (35 mL) at 0° C. Next, triethylamine (10.14 mL, 72.7 mmol) was
added dropwise and the solution was stirred 20 minutes (precipitate
forms) before being transferred to a separatory funnel with DCM and
water. The layers were separated and the organics were washed with water,
1N HCl, saturated aqueous sodium chloride, and dried over sodium sulfate.
The solution was filtered and concentrated in vacuo to give
(E)-(2-nitrovinyl)cyclohexane. The product was used directly for the next
step without further purification. Step 3: Potassium t-butoxide (0.517 g,
4.61 mmol) was added in one portion to a solution of
(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol
(Intermediate X, 1.5 g, 4.39 mmol) in THF (30 mL) at -78° C. After
stirring for 45 minutes, (E)-(2-nitrovinyl)cyclohexane (0.716 g, 4.61
mmol) in THF (15.00 mL) was added slowly via syringe. The reaction was
stirred at -78° C. for 20 minutes and was quenched with acetic
acid (0.502 mL, 8.78 mmol) at -78° C., diluted with saturated
aqueous ammonium chloride, water and EtOAc. After warming to RT, the
layers were seperated and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with water, saturated aqueous
sodium chloride, and dried over sodium sulfate. The solution was filtered
and concentrated in vacuo to give the crude material. The crude material
was purified by silica gel chromatography by eluting with 1:6 to 1:4
EtOAc in hexane, to provide
7-bromo-3-chloro-5-((1-cyclohexyl-2-nitroethoxy)methyl)-5H-chromeno[2,3-c-
]pyridin-5-amine as a yellow oil. [M+H].sup.+=496.1. Step 4: TEA (1.263
ml, 9.06 mmol) and triiodophosphine (1.243 g, 3.02 mmol) were added to
7-bromo-3-chloro-5-((1-cyclohexyl-2-nitroethoxy)methyl)-5H-chromeno[2,3-c-
]pyridin-5-amine (1.5 g, 3.02 mmol) in DCM (30.2 ml) at 0° C. The
reaction was stirred 10 minutes before the ice water bath was removed and
the reaction was allowed to come to RT. After 1.5 hours, the solution is
cooled to 0° C. and quenched with saturated aqueous sodium
bicarbonate, diluted with water, and extracted with DCM. The combined
organic extracts were washed with 1N NaOH, water, saturated aqueous NaCl,
and dried over sodium sulfate. The solution was filtered and concentrated
in vacuo to give the crude material. The crude material was purified by
silica gel chromatography by eluting with 1:4 EtOAc in hexane, to provide
2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)-2-cy-
clohexylacetonitrile, [M+H]=462.0. Step 5: Trimethylaluminum, as a 2 M
solution in toluene, (0.973 ml, 1.947 mmol) was added dropwise via
syringe to a solution of
2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)-2-cy-
clohexylacetonitrile (0.563 g, 1.217 mmol) in DCE (12 ml) at RT. After
stirring 14 hours, the reaction was cooled to 0° C. and 1 N aq.
HCl (12 ml, 12 mmol) was added dropwise via syringe (slowly at first
until vigorous reaction subsided) and the mixture was stirred at
0° C. for 10 minutes and then at RT before being diluted with DCM.
The layers were separated and the aqueous layer was extracted with DCM.
The combined organic extracts were washed with 1 N aq. NaOH, saturated
aqueous sodium chloride, and dried over sodium sulfate. The solution was
filtered and concentrated in vacuo to give the crude material. The crude
material was purified by silica gel chromatography by eluting with 1:20
MeOH in DCM, to provide
7-bromo-3-chloro-6'-cyclohexyl-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-
-5,3'-[1,4]oxazin]-5'-amine as a mixture of racemic diastereomers.
[M+H]=462.0. Step 6: A glass microwave reaction vessel was charged with
7-bromo-3-chloro-6'-cyclohexyl-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-
-5,3'-[1,4]oxazin]-5'-amine (0.075 g, 0.162 mmol), 2 M aqueous sodium
carbonate (0.8 mL, 1.600 mmol), and dioxane (1.6 mL). The vessel was
capped and the solution was degassed by bubbling nitrogen gas through the
solution for 10 minutes. Next, Pd(PPh3)4 (7.49 mg, 6.48
μmol) and (2-fluoropyridin-3-yl)boronic acid (0.027 g, 0.194 mmol)
were added and the vessel was sealed. The reaction mixture was stirred
and heated in a Initiator microwave reactor (Personal Chemistry, Biotage
AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The reaction
was poured into water and the mixture was extracted with EtOAc. The
combined organic extracts were washed with water, saturated aqueous
sodium chloride, and dried over sodium sulfate. The solution was filtered
and concentrated in vacuo to give the crude material. The crude material
was purified by silica gel chromatography by eluting with 1:20 MeOH in
DCM, to provide the product as a racemic mixture of diastereomers. The
diastereomers were seperated by reverse-phase preparative HPLC using a
Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm,
0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 20 min to
provide racemic (3'R,
6'S)-3-chloro-6'-cyclohexyl-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[c-
hromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine and racemic (3'S,
6'S)-3-chloro-6'-cyclohexyl-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[c-
hromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine each as a white solid
after isolating the free base by partitoning between DCM and 1 N NaOH.
[M+H].sup.+=479.1 for each racemic diastereomer pair.

[0598] Step 1: A vial charged with Pd2(dba)3 (0.150 g, 0.164
mmol), XPhos (0.391 g, 0.819 mmol), 5-(tributylstannyl)pyrimidine (1.81
g, 4.92 mmol), 2-bromo-7-methoxy-9H-xanthen-9-one (1.000 g, 3.28 mmol)
and dioxane (10 mL). The reaction mixture was evacuated and backfilled
with nitrogen. The reaction mixture was heated to 100° C.
overnight. The reaction mixture was cooled to RT and diluted with water
and EtOAc. A grey solid precipitated out, which was filtered off. The
solid was washed with EtOAc and water. The grey solid dried under reduced
pressure to afford 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one) (0.600
g, 60.2% yield). Step 2: A solution of vinylmagnesium chloride (1.6M
solution in THF; 0.82 mL, 1.314 mmol) was added dropwise to a solution of
2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one (200 mg, 0.657 mmol) in THF
(10 mL) at -78° C. After 30 min, the reaction mixture was allowed
to warm to -10° C. and was then quenched with saturated aqueous
ammonium chloride. The reaction was extracted with EtOAc, and the organic
phase was dried over sodium sulfate, and concentrated under reduced
pressure. The residue was purified by chromatography to give
2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol as a pale yellow
gum. Step 3: 2 N HCl (3 mL) was added to solution of
2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol)
and thiourea (9.25 pt, 0.171 mmol) in HOAc (5 mL). The reaction mixture
was allowed to stir overnight at rt and concentrated under reduced
pressure. The residue was treated with of TFA (4 mL). The reaction
mixture was stirred overnight at rt. The reaction mixture was
concentrated under reduced pressure and the residue was treated with
aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and
concentrated under reduced pressure. The residue was purified by
chromatography (DCM/MeOH 20:1 to 5:1) to give
2'-methoxy-7'-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthe-
n]-2-amine as an off-white solid.

[0600] Step 1: A suspension of cesium carbonate (41.1 g, 126 mmol),
2,6-difluoropyridine (11.01 mL, 121 mmol) and morpholine (10.00 mL, 115
mmol) in ACN (100 mL) was heated to 70° C. for 12 hours in a
sealed vessel. The reaction mixture was cooled to RT and filtered. The
obtained filtrate was concentrated under reduced pressure. The crude
material was purified by silica gel chromatography (5-25% EtOAc/hexanes)
to provide 13.7 g, of 4-(6-fluoropyridin-2-yl)morpholine. Step 2:
Chlorosuccinimide (10.29 g, 77 mmol) was added to a solution of
4-(6-fluoropyridin-2-yl)morpholine (11.7 g, 64.2 mmol) in ACN (15 mL).
The reaction mixture was heated to 70° C. for 30 min. Water and
DCM were added. The organic phase was separated, washed with aqueous
NaHCO3, brine and subsequently dried over MgSO4. The solvent
was removed under reduced pressure and the residue was purified by silica
gel chromatography (5-20% EtOAc/hexanes) to afford 3.11 g of
4-(5-chloro-6-fluoropyridin-2-yl)morpholine. Step: A solution of
2,2,6,6-tetramethylpiperidine (1.897 mL, 11.24 mmol) in THF (45 mL) was
cooled to -78° C. and treated with n-BuLi (1.6M in hexanes) (6.77
mL, 10.83 mmol) under nitrogen atmosphere. The solution was warmed to
0° C. and stirred at that temperature for 25 minutes. The solution
was cooled back down to -78° C. and treated with a solution of
4-(5-chloro-6-fluoropyridin-2-yl)morpholine (2.165 g, 9.99 mmol) in THF
(11.25 mL) under nitrogen atmosphere. The solution was allowed to stir at
that temperature for 40 minutes and then added drop wise via cannula to a
solution of (S)-ethyl
2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate
(3.5 g, 8.33 mmol) in THF (11.25 mL) also cooled to -78° C. under
nitrogen atmosphere. The reaction mixture was allowed to stir at
-78° C. for additional 2 hours and then quenched with acetic acid
(0.715 mL, 12.49 mmol). The reaction mixture was allowed to warm to RT
overnight. The solvent was removed under reduced pressure and the crude
material was purified by silica gel chromatography (10-60% EtOAc/hexane)
to afford 3.56 g (S)-ethyl
2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(3-chloro-2-fluoro-6-morpholinopyr-
idin-4-yl)-24(S)-1,1-dimethylethylsulfinamido)acetate. Step 4: A solution
of (S)-ethyl
2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(3-chloro-2-fluoro-6-morpholinopyr-
idin-4-yl)-2-((S)-1,1-dimethylethylsulfinamido)acetate (3.56 g, 5.59 mmol)
in THF (60 mL) was cooled to 0° C. and treated drop wise with
DIBAL (1M in THF) (22.36 mL, 22.36 mmol) under nitrogen atmosphere. After
1 h additional 10 mL DIBAL solution were added at RT. After 12 h at RT
additional 10 mL DIBAL solution were added. After 30 min aqueous
saturated solution of potassium sodium tartrate was added, followed by
EtOAc. The reaction mixture was allowed to stir vigorously for 1 h. The
organic phase was separated, washed with aqueous saturated solution of
potassium sodium tartrate and dried over MgSO4. The solvent was
removed under reduced pressure and the crude material was purified by
silica gel chromatography (20-100% EtOAc/hexane) to provide 1.90 g of
(S)--N--((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6--
morpholinopyridin-4-yl)-2-hydroxyethyl)-2-methylpropane-2-sulfinamide.
Step 5: Lithium hydroxide hydrate (0.402 g, 9.58 mmol) was added to a
solution of
(S)--N--((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6--
morpholinopyridin-4-yl)-2-hydroxyethyl)-2-methylpropane-2-sulfinamide (1.9
g, 3.19 mmol) in THF (25 mL) at RT, followed by bromoacetonitrile (0.445
mL, 6.39 mmol). The reaction mixture was allowed to stir at RT for 12 h.
The reaction mixture was treated with aqueous saturated ammonium
chloride, and the mixture was extracted with EtOAc. The organic phase was
washed with water, brine, dried over MgSO4 and then concentrated
under reduced pressure. The remaining residue was purified by silica gel
chromatography (50-100% EtOAc/hexanes) to afford 1.51 g of
(S)--N--((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6--
morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinami-
de. Step 6-7: A solution of hydrogen chloride (5-6N in iPrOH; 1.025 mL,
5.12 mmol) was added to a solution of
(S)--N--((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6--
morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinami-
de (1083 mg, 1.708 mmol) in THF (4 mL) under nitrogen atmosphere. The
reaction mixture was stirred for 10 min at RT. The solvent was removed
under reduced pressure and the residue was dissolved in DCE (2 mL). A
solution of AlMe3 (2M in toluene; 2.56 mL, 5.12 mmol) was added drop
wise and the reaction mixture was allowed to stir at 70 C for 3 h. The
reaction mixture was cooled to RT and a solution of aqueous saturated
solution of potassium sodium tartrate was added, followed by EtOAc. The
reaction mixture was allowed to stir vigorously for 1 h. The organic
phase was separated, washed with brine and dried over MgSO4. The
solvent was removed under reduced pressure and the residue was purified
by silica gel chromatography (100% EtOAc) to afford 390 mg of
(S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-dihydro-
-2H-1,4-oxazin-3-yl)-4-bromophenol. Step 8: A sealable vial was charged
with (S)-2-(5-amino-3-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-3,6-di-
hydro-2H-1,4-oxazin-3-yl)-4-bromophenol (234 mg, 0.482 mmol), cesium
carbonate (471 mg, 1.445 mmol) and copper chloride (9.54 mg, 0.096 mmol
The vial was evacuated and back-filled with nitrogen. NMP (1.5 mL) was
added and the vial was evacuated and backfilled with nitrogen.
2,2,6,6-Tetramethyl-3,5-heptanedione (0.080 mL, 0.385 mmol) was added and
the reaction mixture was heated to 120° C. for 1 h. The reaction
mixture was cooled to room temperature, diluted with EtAOc and filtered
through a pad of silica gel. The solvent was removed under reduced
pressure and the residue was purified by preparative reversed-phase
preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110
Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to
100% over 20 min to obtain 68 mg of
(S)-7-bromo-1-fluoro-3-morpholino-2',6'-dihydrospiro[chromeno[2,3-c]pyrid-
ine-5,3'-[1,4]oxazin]-5'-amine.TFA. Step 9: A sealable vial was charged
with (S)-7-bromo-1-fluoro-3-morpholino-2',6'-dihydrospiro[chromeno[2,3-c]-
pyridine-5,3'-[1,4]oxazin]-5'-amine (50 mg, 0.111 mmol),
2-fluoropyridin-3-ylboronic acid (31.4 mg, 0.223 mmol),
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(7.88 mg, 0.011 mmol) and potassium phosphate (0.028 mL, 0.334 mmol). The
vial was evacuated and backfilled with nitrogen (procedure was repeated
twice). Dioxane (1.3 mL) and water (0.433 mL) were added and the reaction
mixture was purged for 1 min with nitrogen. The vial was placed in a
preheated oil bath (100° C.) for start 2.5 h. The reaction mixture
was cooled to RT and the solvent was removed under reduced pressure. The
residue was purified by preparative reversed-phase preparative HPLC using
a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm,
0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 20 min to
obtain 39 mg of
(S)-1-fluoro-7-(2-fluoropyridin-3-yl)-3-morpholino-2',6'-dihydrospiro[chr-
omeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine 2,2,2-trifluoroacetate as
a light-yellow powder. MS m/z=466.0 [M+H] Calculated for
C24H21F2N5O3.C2HF3O2: 579.48 (TFA
salt).

[0602] Step 1: A solution of neopentyl alcohol (1.065 mL, 9.81 mmol) in
DMSO (82 mL) was cooled to 0° C. NaH (60% in mineral oil; 0.490 g,
12.26 mmol) were added in one portion, the reaction mixture was warmed to
rt and stirred for 20 minutes. 2,6-Difluoropyridine (0.941 mL, 8.175
mmol) was added and the reaction mixture was stirred at overnight. The
reaction mixture was quenched with aqueous, saturated ammonium chloride
solution, diluted with water and EtOAc. The organic layer was separated,
washed with brine and dried over sodium sulfate. The solvent was removed
under reduced pressure to afford 2-fluoro-6-(neopentyloxy)pyridine (1.48
g, 8.08 mmol) as a colorless liquid. Step 2: N-bromosuccinimide (8.29 g,
46.6 mmol) was added to a solution of 2-fluoro-6-(neopentyloxy)pyridine
(7.11 g, 38.8 mmol) in acetonitrile (80 mL) at rt. The reaction mixture
was heated to 70° C. overnight. The reaction mixture was cooled to
rt and the solvent was removed under reduced pressure. The residue was
dissolved in DCM and washed with water. The organic layer was separated,
dried over sodium sulfate and concentrated under reduced pressure. The
residue was purified by flash chromatography (100% hexanes) to obtain
3-bromo-2-fluoro-6-(neopentyloxy)pyridine (5.27 g, 20.11 mmol) as a white
solid. Step 3: A solution of 3-bromo-2-fluoro-6-(neopentyloxy)pyridine
(5.6 g, 21.36 mmol) in THF (50 mL) was cooled to -100° C. and a
solution of n-butyllithium (1.6M in hexane; 14.69 mL, 23.50 mmol) was
added drop wise. The reaction mixture was allowed to stir for 10 min at
-100° C. Triisopropyl borate (7.35 mL, 32.0 mmol) was added and
the reaction mixture was allowed to warm to rt. Aqueous NaOH solution
(5M; 29.9 mL, 150 mmol) was added, followed by hydrogen peroxide (30%;
15.28 mL, 150 mmol). The reaction mixture was allowed to stir for 30 min
at rt. The reaction mixture was acidified with 2N HCl and extracted with
EtOAc. The organic phase was separated and dried over MgSO4. The
solvent was removed under reduced pressure, the residue was dissolved in
acetone (50 mL) and the solution was cooled to 0° C.
K2CO3 (3.25 g, 23.50 mmol) was added, followed by chloromethyl
methyl ether (1.785 mL, 23.50 mmol). After 30 min, additional
K2CO3 (3.25 g, 23.50 mmol) and chloromethyl methyl ether (1.785
mL, 23.50 mmol) were added and the reaction mixture was warmed to rt.
After 2 h brine and diethyl ether were added. The organic was separated
and dried over magnesium sulfate. The solvent was removed under reduced
pressure. The residue was purified by flash chromatography (0-20%
EtOAc/hexanes) to yield
2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine (2.88 g, 11.84
mmol). Step 4: A solution of n-butyllithium (1.6M in hexanes; 6.52 mL,
10.44 mmol) was added drop wise to a solution of
2,2,6,6-tetramethylpiperidine (1.897 mL, 11.24 mmol) in THF (30 mL) at
-78° C. under nitrogen atmosphere. The reaction mixture was warmed
to 0° C. and stirred for 25 min. The reaction mixture was cooled
down again to -78° C. and a solution of
2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine (2.149 g, 8.83 mmol)
in THF (5 mL) was added drop wise. The reaction mixture was kept for 1 h
at -78° C., after which a solution of 5-bromo-2-fluorobenzaldehyde
(1.63 g, 8.03 mmol) in THF (5 mL) was added. The reaction mixture was
allowed to warm up to rt. Aqueous, saturated NH4Cl solution was
added, followed by EtOAc. The organic phase was separated and dried over
MgSO4. The solvent was removed under reduced pressure and the
residue was dissolved in DCM (75 mL). 4-Methylmorpholine 4-oxide (1.176
g, 10.04 mmol) followed by tetrapropylammonium perruthenate (0.141 g,
0.401 mmol) were added. The reaction mixture was allowed to stir for 2 h
at rt. The reaction mixture was filtered through a pad of celite and the
solvent was removed under reduced pressure. The residue was purified by
flash chromatography (5-20% EtOAc/hexanes) to yield
(5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyri-
din-4-yl)methanone as a white solid. Step 5: A solution of
(5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyri-
din-4-yl)methanone (1.89 g, 4.25 mmol) in DCM (20 mL) was cooled to
-78° C. under nitrogen atmosphere. Boron tribromide (1.0M in
CH2Cl2; 4.25 mL, 4.25 mmol) was added drop wise and the
reaction mixture was stirred for 5 min at rt. Aqueous, saturated ammonium
chloride solution was added, followed by water and DCM. The organic phase
was separated and dried over magnesium sulfate. The solvent was removed
under reduced pressure to afford a yellow solid, which was dissolved in
ACN (20.00 mL). Cesium carbonate (1.386 g, 4.25 mmol) was added in one
portion and the reaction mixture was allowed to stir for 5 min. Water was
added and the remaining light-yellow solid was filtered off and dried to
afford 7-bromo-1-fluoro-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridin-5-one
(1.27 g). Step 6: To a suspension of
7-bromo-1-fluoro-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridin-5-one (1000
mg, 2.63 mmol) in THF (25 mL) at -40° C. was added drop wise
((trimethylsilyl)methyl)lithium (1.0M solution in pentane; 3.95 mL, 3.95
mmol). After 10 min, TFA (0.304 mL, 3.95 mmol) was added drop wise and
the reaction mixture was allowed to warm to rt Additional 1 ml of TFA was
added and the reaction mixture was allowed to stir for 1 hour at P. An
aqueous, saturated K2CO3 solution was added, followed by EtOAc.
The organic phase was separated and dried over Na2SO4. The
solvent was removed under reduced pressure to yield
7-bromo-1-fluoro-5-methylene-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridine
as a yellow solid (995 mg), which was used in the next step without
further purification. Step 7: To a solution of
7-bromo-1-fluoro-5-methylene-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridine
(995 mg, 2.63 mmol) in THF (60 mL)/Water (10 mL) was added iodine (1335
mg, 5.26 mmol) and silver oxide (1219 mg, 5.26 mmol). The reaction
mixture was allowed to stir at rt for 20 min. K2CO3 (545 mg,
3.95 mmol) was added in one portion and the reaction mixture was allowed
to stir for 30 min. The reaction mixture was filtered through a pad of
celite. The reaction mixture was partitioned between water and EtOAc. The
organic phase was separated, dried over Na2SO4. The solvent was
removed under reduced pressure to afford
7-bromo-1-fluoro-3-(neopentyloxy)spiro[chromeno[2,3-c]pyridine-5,2'-oxira-
ne] as a yellow solid (1000 mg) which was taken onto the next step without
further purification. Step 8:
7-Bromo-1-fluoro-3-(neopentyloxy)spiro[chromeno[2,3-c]pyridine-5,2'-oxira-
ne] (1000 mg, 2.54 mmol) was dissloved in DMF (16 mL) and
azidotrimethylsilane (2.020 mL, 15.22 mmol) was added drop wise. The
reaction mixture was allowed to stir at rt for 1 h. Water and EtOAc were
added, the organic layer was separated and dried over MgSO4. The
solvent was removed under reduced pressure to afford an oil which was
dissolve in THF (20 mL) and cooled to 0° C. Lithium aluminum
hydride (1.0M in THF; 3.27 mL, 3.27 mmol) was added drop wise. After 1 h
additional 1.5 mL of LiAlH4 solution were added and the reaction
mixture was allowed to stir for additional 10 min at 0° C. The
reaction mixture was quenched with an aqueous, saturated solution of
Rochelle's salt. Water and EtOAc were added. The organic phase was
separated and dried over Na2SO4. The solvent was removed under
reduced pressure and the crude product was taken onto the next step
without further purification. Step 9: To a solution of
(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methano-
l (1 g, 2.78 mmol) in THF (2 mL) was added simultaneously and drop wise
lithium tert-butoxide (1.0 M in THF; 4.73 mL, 4.73 mmol) and a solution
of bromoacetonitrile (0.329 mL, 4.73 mmol) in THF (2 mL) at RT.
Additional lithium tert-butoxide (1.0 M in THF; 4.73 mL, 4.73 mmol) and a
solution of bromoacetonitrile (0.329 mL, 4.73 mmol) in THF (2 mL) were
added after 1 hour, 2 hours and 3 hours reaction time, respectively. The
reaction mixture was quenched with aqueous, saturated NH4Cl solution
and 2M HCl. EtOAc was added and the organic phase was separated and dried
over MgSO4. The solvent was removed under reduced pressure and the
residue was taken onto the next step without further purification. Step
10: 2-45-Amino-7-bromo-1-fluoro-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridi-
n-5-yOmethoxy)-acetonitrile (1000 mg, 2.221 mmol) was dissolved in DCE (4
mL) and trimethylaluminum solution (2M in toluene; 2.221 mL, 4.44 mmol)
was added drop wise. The reaction mixture was heated to 70° C. for
15 min. The reaction mixture was cooled to rt. Aqueous, saturated
solution of Rochelle's salt was added, followed by EtOAc. The organic
phase was separated, washed with brine and dried over MgSO4. The
solvent was removed under reduced pressure and the residue was purified
by flash chromatography (10-100% EtOAc/hexanes) to afford
7-bromo-1-fluoro-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyrid-
ine-5,3'-[1,4]oxazin]-5'-amine as a light-brown solid. Step 11: A sealable
vial was charged with
7-bromo-1-fluoro-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyrid-
ine-5,3'-[1,4]oxazin]-5'-amine (200 mg, 0.444 mmol),
2-fluoropyridin-3-ylboronic acid (125 mg, 0.888 mmol),
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(31.4 mg, 0.044 mmol) and potassium phosphate (283 mg, 1.332 mmol). The
vial was evacuated and backfilled with nitrogen (procedure was repeated
twice). Dioxane (3 mL) and water (1 mL) were added and the reaction
mixture was purged for 1 min with nitrogen. The vial was placed in a
preheated oilbath (100° C.) for start 1.5 h. The reaction mixture
was cooled to rt and water and EtOAc were added to the reaction mixture.
The organic phase was separated and dried over MgSO4. The solvent
was removed under reduced pressure and the residue was purified by column
chromatography (1-10% MeOH in DCM) to obtain
1-fluoro-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro[chr-
omeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine as a beige solid (185 mg).
Step 12: Compounds
(R)-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro-
[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (Example 59B) and
(S)-1-fluoro-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro-
[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine (Example 59A) were
obtained from racemic
1-fluoro-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2',6'-dihydrospiro[chr-
omeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine using similar chiral
separation conditions as described herein for intermediate 10. Mass for
both peaks m/z=467.0 [M+H].sup.+. Calculated for
C25H24F2N4O3: 466.18

[0609] Step 1: In a 25-mL flask, the
(R)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]py-
ridine-5,4'-[1,3]oxazin]-2'-amine (0.350 g, 0.793 mmol) was suspended in
1,1-dimethoxy-N,N-dimethylmethanamine (5.29 mL, 39.7 mmol). The reaction
mixture was heated to 100° C. for 1 h. The reaction was
concentrated, and the residue was taken up in 5% MeOH/DCM (60 mL) and the
organic phase was extracted with dilute brine (2×8 mL), then was
dried over sodium sulfate and concentrated. The residue was purified by
chromatography (3.5% MeOH/DCM) to afford
(R,E)-N'-(3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,-
3-b]pyridine-5,4'-[1,3]oxazin]-2'-yl)-N,N-dimethylformimidamide (394 mg,
0.793 mmol). Step 2: In a 100-mL resealable vessel, the potassium acetate
(0.234 g, 2.381 mmol), PdCl2-dppf-DCM (0.065 g, 0.079 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.242 g,
0.953 mmol),
(R,E)-N'-(3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,-
3-b]pyridine-5,4'-[1,3]oxazin]-2'-yl)-N,N-dimethylformimidamide (0.394 g,
0.794 mmol) was suspended in THF (8 mL). Argon was blown through the
vessel, which was then sealed and heated in an 85° C. oil bath for
14 h. The vessel was removed from the oil bath and cooled to 0°
C., and aqueous NaOH (2.5 M, 1.905 mL, 4.76 mmol) was added, followed by
aqueous 30% hydrogen peroxide (0.811 mL, 7.94 mmol). The ice bath was
removed, and the mixture was stirred for 45 min. The mixture was
concentrated to remove most of the THF. The residue was taken up in 10%
MeOH/DCM (600 mL), and the organic layer was extracted with dilute brine
(2×15 mL). The organic layer was dried with magnesium sulfate,
filtered, and concentrated. The crude
(R,E)-N'-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5',6'-dihydrospiro[chromeno[-
2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-yl)-N,N-dimethylformimidamide was used
in the next step without further purification. Step 3: In a 35-mL
resealable vessel, cesium carbonate (0.621 g, 1.905 mmol),
1-iodo-2,2-dimethylpropane (0.211 mL, 1.587 mmol), and crude
(S,E)-N'-(7-(2-fluoropyridin-3-yl)-3-hydroxy-5',6'-dihydrospiro[chromeno[-
2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-yl)-N,N-dimethylformimidamide (0.344
g, 0.794 mmol) were taken up in DMF (8 mL). The vessel was sealed and
heated in a 100° C. oil bath. After 6 h, the reaction was
concentrated. The residue was taken up in 10% MeOH/DCM (120 mL) and the
organic layer was extracted with water (2×10 mL). The organic layer
was dried over MgSO4, filtered and concentrated. The residue was
taken up in dioxane (8 mL), and a dioxane solution of HCl (4 M, 2 mL) was
added. The vessel was sealed and heated in a 60° C. oil bath.
After 1 h, the reaction was concentrated. The residue was diluted with
water (30 mL) and the aqueous phase was extracted with 10% MeOH/DCM
(3×50 mL). The organics were dried over magnesium sulfate,
filtered, and concentrated. The material was purified by chromatography
using 65:35:0.5:1 EtOAc-hexane-MeOH-Et3N to afford
(S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-5',6'-dihydrospiro[chromeno-
[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine (4.5 mg, 0.010 mmol). MS (m/z)
449 (M+H).sup.+.

[0613] Step 1: In a 250-mL flask, the
(R)-2'-bromo-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-ami-
ne (0.393 g, 1.047 mmol) was dissolved in dcm (10 mL). The solution was
cooled to 0° C. A DCM solution of boron tribromide (1.0 M, 3.14
mL, 3.14 mmol) was added. After 1.5 h, the mixture was quenched with 9:1
saturated aqueous NH4Cl/NH4OH (10 mL). The mixture was diluted
further with water (10 mL) and the aqueous phase was extracted with 5%
MeO/DCM (3×50 mL). The organics were combined, washed with dilute
brine (10 mL), dried over sodium sulfate and concentrated to afford crude
(R)-5-amino-2'-bromo-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-7'-ol
(349 mg, 0.966 mmol), which was used directly in the next step. Step 2:
In a microwave vial, potassium phosphate (0.615 g, 2.90 mmol),
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(0.068 g, 0.097 mmol), 2-fluoropyridin-3-ylboronic acid (0.170 g, 1.208
mmol) and (R)-5-amino-2'-bromo-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol (0.349 g, 0.966 mmol) were suspended in dioxane (8 mL). Water (2
mL) was added, and argon gas was blown through the vessel, which was then
sealed and heated in a 100° C. oil bath for 3 h. The reaction was
concentrated to remove the dioxane. The residue was diluted with aqueous
NH4Cl (15 mL) and the aqueous phase was extracted with 5% MeOH/DCM
(3×33 mL). The organics were combined, washed with dilute brine (8
mL), dried over sodium sulfate and concentrated to afford crude
(S)-5-amino-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'--
xanthen]-7'-ol which was used directly in the next step. Step 3: In a
250-mL flask, the crude
(S)-5-amino-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'--
xanthen]-7'-ol (0.365 g, 0.967 mmol) was dissolved in THF (10 mL).
Boc2o (0.232 g, 1.06 mmol) was added, followed by TEA (0.148 mL,
1.06 mmol). After 1 h The reaction was concentrated to afford crude
(5)-tert-butyl
2'-(2-fluoropyridin-3-yl)-7'-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-x-
anthene]-5-ylearbamate, which was used directly in the next step. Step 4:
In a 100-mL flask, crude (5)-tert-butyl
2'-(2-fluoropyridin-3-yl)-7'-hydroxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-x-
anthene]-5-ylearbamate (0.462 g, 0.968 mmol) was dissolved in DCM (10 mL).
The solution was cooled to 0° C., and
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
(0.513 g, 1.43 mmol) and triethylamine (0.243 mL, 1.74 mmol) were added.
After 3 h, the reaction was concentrated and material was purified by
chromatography (33% EtOAc/hexanes) to afford
(S)-5-(tert-butoxycarbonylamino)-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospi-
ro[[1,4]oxazine-3,9'-xanthene]-7'-yl trifluoromethanesulfonate (0.293 g,
0.481 mmol). Step 5: In a microwave vial,
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.062 g, 0.297 mmol),
(S)-5-(tert-butoxycarbonylamino)-2'-(2-fluoropyridin-3-yl)-2,6-dihydrospi-
ro[[1,4]oxazine-3,9'-xanthene]-7'-yl trifluoromethanesulfonate (0.145 g,
0.238 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.024
mmol) were taken up in DMF (3 mL). Aqueous sodium carbonate (1.0 M, 0.714
mL, 0.714 mmol) was added. Argon was blown through the vessel which was
sealed and placed in an 85° C. oil bath. After 3 h, the reaction
was concentrated. The residue was diluted with water (15 mL) and the
aqueous phase was extracted with 3% MeOH/DCM (3×25 mL). The
organics were combined, washed with brine (7 mL), dried over sodium
sulfate and concentrated. The residue was transferred to a microwave vial
with 3 mL of DCMm and tfa (0.275 mL, 3.57 mmol) was added. The vial was
sealed and the reaction was stirred in a 65° C. oil bath for 2 h.
The reaction was concentrated. The residue was neutralized with 0.5 M
Na2CO3 (13 mL). The aqueous phase was extracted with 5%
MeOH/DCM (3×25 mL). The organics were combined, washed with dilute
brine (8 mL), dried over sodium sulfate and concentrated. The residue was
purified by chromatography (7%-8% MeOH/DCM) to afford
(R)-2'-(3,6-dihydro-2H-pyran-4-yl)-7'-(2-fluoropyridin-3-yl)-2,6-dihydros-
piro[[1,4]oxazine-3,9'-xanthen]-5-amine (65 mg, 0.146 mmol).

[0620] Step 1: In a 500-mL flask, the
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine (0.676 g, 1.719 mmol) was suspended in dcm (50 mL). The
suspension was cooled to 0° C., and a DCM solution of
tribromoborane (1.0 M, 5.16 mL, 5.16 mmol) was added. After 1.5 h, the
reaction was quenched with 9:1 aqueous NH4Cl/NH4OH (20 mL). The
aqueous phase was extracted with 5% MeOH/DCM (3×50 mL). The
organics were combined, washed with brine (15 mL), dried over sodium
sulfate and concentrated to afford crude
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol (604 mg, 1.593 mmol) which was used directly in the next step.
Step 2: In a microwave vial, the potassium phosphate (1.014 g, 4.78
mmol), PdCl2(AmPhos)2 (0.085 g, 0.119 mmol),
(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen-
]-7'-ol (0.604 g, 1.593 mmol), and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.485 g, 2.310 mmol) were suspended in dioxane (6.5 mL) and water (2.5
mL). Argon gas was blown through the vessel, which was sealed and heated
by microwave at 120° C. for 30 min. The mixture was concentrated.
The residue was neutralized with half-saturated aqueous NH4Cl (35
mL). The aqueous phase was extracted with 5% MeOH/DCM (3×35 mL).
The organics were combined, washed with dilute brine (15 mL), dried over
sodium sulfate and concentrated to afford crude
(S)-5-amino-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-2,6-dihydrospiro[[1,-
4]oxazine-3,9'-xanthen]-7'-ol which was used directly in the next step.
Step 3: In a 250-mL flask, the crude
(S)-5-amino-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-2,6-dihydrospiro[[1,-
4]oxazine-3,9'-xanthen]-7'-ol (0.609 g, 1.593 mmol) was suspended in THF
(30 mL). Boc2O (0.564 g, 2.58 mmol) was added, followed by
triethylamine (0.373 mL, 2.69 mmol). The mixture was stirred at rt. After
1.5 h, the reaction was concentrated to afford crude (S)-tert-butyl
2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-7'-hydroxy-2,6-dihydrospiro[[1,4-
]oxazine-3,9'-xanthene]-5-ylcarbamate which was used directly in the next
step. Step 4: In a 250-mL flask, the (S)-tert-butyl
2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-7'-hydroxy-2,6-dihydrospiro[[1,4-
]oxazine-3,9'-xanthene]-5-ylcarbamate (0.768 g, 1.592 mmol) was dissolved
in DCM (25 mL). The solution was cooled to 0° C. TEA (0.533 mL,
3.85 mmol) was added, followed by
1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
(1.25 g, 3.50 mmol). After 2 h, the reaction was concentrated. Without
working it up, the residue was purified by chromatography (25%
EtOAc/hexanes) to afford
(S)-5-(tert-butoxycarbonylamino)-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-
-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7'-yl
trifluoromethanesulfonate (436 mg, 0.709 mmol). Step 5: In a microwave
vial, diisopropyl 5-(prop-1-ynyl)pyridin-3-ylboronate (0.109 g, 0.443
mmol), (S)-5-(tert-butoxycarbonylamino)-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-
-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthene]-7'-yltrifluoromethane-
sulfonate (0.218 g, 0.355 mmol), and Pd(PPh3)4 (0.041 g, 0.035
mmol) were taken up in DMF (3.7 mL). Aqueous sodium carbonate (1.0 M,
1.064 mL, 1.064 mmol) was added. Argon gas was blown through the vessel,
which was sealed and heated in an 85° C. oil bath for 1.5 h. The
reaction was concentrated. The residue was taken up in water (10 mL) and
the aqueous phase was extracted with 5% MeOH/DCM (3×20 mL). The
organics were combined, washed with dilute brine (5 mL), dried over
sodium sulfate and concentrated. The residue was transferred to a
microwave vial in DCM (2 mL), and TFA (0.683 mL, 8.87 mmol) was added.
The vessel was sealed and heated in a 50° C. oil bath for 1.5 h.
The reaction was concentrated, and the residue was neutralized with 0.5 M
aqueous Na2CO3 (15 mL). The aqueous phase was extracted with 5%
MeOH/DCM (3×20 mL). The organics were combined, washed with dilute
brine (6 mL), dried over sodium sulfate and concentrated. The residue was
purified by chromatography (7% MeOH/DCM) to afford
(S)-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-7'-(5-(prop-1-ynyl)pyridin-3-
-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine (98 mg, 0.203
mmol).

[0623] Step 1: In a 25-mL flask, the
2'-bromo-7'-methoxyspiro[morpholine-3,9'-xanthen]-5-one (0.094 g, 0.250
mmol) was dissolved in DCM (5 mL). The solution was cooled to -78°
C., and a solution of boron tribromide (1.0 M, 0.750 mL, 0.750 mmol) in
DCM was added. The mixture was warmed to 0° C. and held at that
temperature for 2 h. The reaction was diluted with water (20 mL) and the
aqueous phase was extracted with 3% MeOH/DCM (3×25 mL). The
organics were combined, washed with dilute brine (5 mL), dried over
sodium sulfate, and concentrated. The residue was purified by
chromatography (70:30:1 EtOAc/hexane/MeOH) to afford
(R)-2'-bromo-7'-hydroxyspiro[morpholine-3,9'-xanthen]-5-one. Step 2: In a
25-ml flask, 2'-bromo-7'-hydroxyspiro[morpholine-3,9'-xanthen]-5-one
(0.020 g, 0.055 mmol) was dissolved in DMF (1 mL). Cesium carbonate
(0.043 g, 0.133 mmol) was added, followed by 1-iodo-2,2-dimethylpropane
(0.022 g, 0.110 mmol). The reaction was heated in a 115° C. oil
bath for 10 h. The reaction was cooled to ambient temperature and
concentrated. The residue was taken up in 0.3 M aqueous HCl (15 mL) and
the aqueous layer was extracted with EtOAc (3×20 mL). The organic
layers were combined, washed with saturated brine (5 mL), dried over
sodium sulfate, and concentrated. The residue was purified by
chromatography (25% EtOAc/hexane) to afford
(R)-2'-bromo-7'-(neopentyloxy)spiro[morpholine-3,9'-xanthen]-5-one. Steps
3 and 4: (R)-2'-Bromo-7'-(neopentyloxy)spiro[morpholine-3,9'-xanthen]-5-o-
ne (0.0068 g, 0.016 mmol) was converted to
(3R)-2'-bromo-7'-(2,2-dimethylpropoxy)-6H-spiro[1,4-oxazine-3,9'-xanthen]-
-5-amine using procedures analogous to that described in steps 1 and 2 in
method A12 (Example 67a). Step 5: In a microwave vessel, potassium
phosphate (0.012 g, 0.056 mmol),
bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II)
(0.985 mg, 1.391 μmol) and 2-fluoropyridin-3-ylboronic acid (5.23 mg,
0.037 mmol) were loaded as solids, and
(3R)-2'-bromo-7'-(2,2-dimethylpropoxy)-6H-spiro[1,4-oxazine-3,9'-xanthen]-
-5-amine (0.008 g, 0.019 mmol) was added via cannula as a solution in
dioxane (1 mL). Water (0.25 mL) was added to the vessel, and the mixture
was purged with argon gas, then the vessel was sealed and heated in
microwave radiation at 135° C. for 30 min. The material was taken
up in water (10 mL) and the aqueous phase was extracted with DCM
(3×20 mL). The organics were combined, washed with dilute brine (5
mL), dried over sodium sulfate, and concentrated. The material was
purified by preparative TLC (13% MeOH/DCM) to afford
(3S)-2'-(2,2-dimethylpropoxy)-7'-(2-fluoro-3-pyridinyl)-6H-spiro[1,4-oxaz-
ine-3,9'-xanthen]-5-amine.

[0626] The following compounds in Table I are additional representative
examples of compounds of Formulas I, I-A, 1-A-1 through 1-A-7, I-B, II,
II-A and II-B provided by the present invention. The methods and
intermediates used to prepare each compound are also included in the
Table, along with the mass found and biological data (average nM
IC50's for the enzyme and cell assays) where available. The names of
the compounds were generated using the naming convention of the ChemDraw
Ultra software, version 11 and above. Where the example is a racemic
mixture, the name for that example includes both enantiomers. Individual
enantiomers of examples are as indicated in the name.

[0629] The title compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 15B,
2-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid. MS
m/z=476.0 [M+H].sup.+. Calculated for
C25H16F3N5O3: 475.13

[0632] The title compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 15B,
2-fluoropyridin-3-ylboronic acid and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0636] The title compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 18B,
2-fluoropyridin-3-ylboronic acid and
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0640] The title compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 15B,
3-pyridylboronic acid and 2-fluoropyridine-4-boronic acid. MS m/z=458.0
[M+H].sup.+. Calculated for C25H17F2N5O2: 457.14

[0647] The title compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 15B,
2-fluoropyridin-3-ylboronic acid and 3-pyridylboronic acid. MS m/z=458.0
[M+H].sup.+. Calculated for C25H17F2N5O2: 457.14

[0650] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using (Intermediate 17B),
2-fluoropyridin-3-ylboronic acid and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0654] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using (Intermediate 17B),
2-fluoropyridin-3-ylboronic acid and 2-methylpyridine-4-boronic acid
pinacol ester.

[0662] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 18B,
2-fluoropyridin-3-ylboronic acid and 5-fluoropyridin-3-ylboronic acid. MS
m/z=458.0 [M+H].sup.+. Calculated for
C25H17F2N5O2: 457.43

[0665] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 18B,
2-fluoropyridin-3-ylboronic acid and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0669] The titled compound was synthesized by steps analogous to those
described in method A2 above, but using intermediate 18B,
2-fluoropyridin-3-ylboronic acid and 3,3-dimethylbut-1-yne. MS m/z=443.0
[M+H].sup.+. Calculated for C26H23FN4O2: 442.48

[0672] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 18B,
2-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid. MS
m/z=458.0 [M+H].sup.+. Calculated for
C25H17F2N5O2: 457.43

[0675] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 18B,
5-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid. MS
m/z=458.0 [M+H].sup.+. Calculated for
C25H17F2N5O2: 457.43

[0678] The titled compound was synthesized by steps analogous to those
described in method A1 above, but using intermediate 18B,
5-fluoropyridin-3-ylboronic acid and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0682] The title compound was synthesized by steps analogous to those
described in method A6 above, but using intermediate 13A,
2-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine. MS m/z=499.0
[M+H].sup.+. Calculated for C26H22F4N4O2: 498.17

[0685] The title compound was synthesized by steps analogous to those
described in method A6 above, but using intermediate 20B,
2-fluoropyridin-3-ylboronic acid and (R)-3-fluoropyrrolidine. MS
m/z=467.0 [M+H].sup.+. Calculated for
C25H21F3N4O2: 466.16

[0687] Synthesis of
(S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'42-fluoropyridin-3-yl)-5,6--
dihydrospiro[[1,3]oxazine-4,9'-xanthen]-2-amine The title compound was
synthesized by steps analogous to those described in method A6 above, but
using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and
(R)-3-fluoropyrrolidine. MS m/z=467.0 [M+H].sup.+. Calculated for
C25H21F3N4O2: 466.16

[0690] The title compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 20B,
2-fluoropyridin-3-ylboronic acid and
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0694] The title compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 20B,
2-fluoropyridin-3-ylboronic acid and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0698] The title compound was synthesized by steps analogous to those
described in method A8 above, but using intermediate 20B,
2-fluoropyridin-3-ylboronic acid and 2-fluoro-2-methylpropyl
trifluoromethanesulfonate.

[0702] The title compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 20B,
2-fluoropyridin-3-ylboronic acid and 3-pyridineboronic acid. MS m/z=457.0
[M+H].sup.+. Calculated for C26H18F2N4O2: 456.14

[0709] The title compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 20B,
2-fluoropyridin-3-ylboronic acid and 4-Pyridineboronic acid. MS m/z=456.8
[M+H]+1. Calculated for C26H18F2N4O2:
456.14

[0712] The title compound was synthesized by steps analogous to those
described in method A8 above, but using intermediate 20B,
pyridin-3-ylboronic acid and 2-fluoro-2-methylpropyl
trifluoromethanesulfonate.

[0716] The title compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 20B,
pyridin-3-ylboronic acid and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0720] The title compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 20B,
pyridin-3-ylboronic acid and
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0724] The title compound was synthesized by steps analogous to those
described in Method A4, but using Intermediate 10B,
3-hydroxy-2,2-dimethylpropanenitrile, and 3-fluorophenylboronie acid. MS
m/z=459.3 [M+H].sup.+. Calculated for C26H23FN4O3:
458.18.

[0727] The title compound was synthesized by steps analogous to those
described in Method A3, but using Intermediate 10B,
5-fluoropyridin-3-ylboronic acid, and 3,3-difluoropyrrolidine
hydrochloride. MS m/z=468.3 [M+H].sup.+. Calculated for
C24H20FN5O2: 467.16.

[0742] The title compound was synthesized by steps analogous to those
described in Method A1, but using Intermediate 10B, pyridin-3-ylboronic
acid, and 3,4-difluorophenylboronic acid. MS m/z=457.2 [M+H].sup.+.
Calculated for C26H18F2N4O2: 456.14.

[0745] The titled compound was synthesized by steps analogous to those
described in method A8 above, but using intermediate 23 and obtained from
racemic 4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-
-5,6-dihydrospiro[[1,3]thiazine-4,9'-xanthen]-2-amine using similar chiral
separation conditions as described herein for intermediate 10.

[0749] The titled compound was synthesized by steps analogous to those
described in method A7 above, but using intermediate 23 and
2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
(S)-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5,-
6-dihydrospiro[[1,3]thiazine-4,9'-xanthen]-2-amine (>99% ee) was
obtained from racemic
2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5,6-di-
hydrospiro[[1,3]thiazine-4,9'-xanthen]-2-amine using similar chiral
separation conditions as described herein for intermediate 10.

[0782] The titled compound was synthesized by steps analogous to those
described in method A37 except that 2-fluoropyridin-3-ylboronic acid was
used in Step 5,
(S)-2'-bromo-4'-fluoro-7'-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9'-xant-
hen]-5-amine was converted to
(S)-2'-(5,6-dihydro-2H-pyran-3-yl)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2,-
6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine. MS (m/z) 462
(M+H).sup.+.

[0785] The titled compound was synthesized by steps analogous to those
described in method A32 (except that 3,3-dimethylbut-1-yne was used, and
diisopropylamine was used instead of TBAF-(H2O)3), Intermediate
26B was converted to
(S)-3-(3,3-dimethylbut-1-ynyl)-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospir-
o[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine. MS (m/z) 443
(M+H).sup.+.

[0787] The present invention also provides methods for making compounds of
Formulas I-II, and sub-formulas thereof. For example, and in addition to
the methods described herein, the compounds of the invention may be made
by the methods similar to those described in the literature references
cited below.

##STR00135##

[0788] In one embodiment of the invention, there is provided a method of
making a compound of Formula I, the method comprising the step of
reacting a compound 20

##STR00136##

wherein A1, A2, A3, A4, A5, A6, R2, X,
Y and Z of Formula I are as defined herein, with a compound having the
structure

##STR00137##

or R7--B(OH)2, wherein R7 is as defined herein, to make a
compound of Formula I.

[0789] In another embodiment of the invention, there is provided a method
of making a compound of Formula I-A, the method comprising the step of
reacting a compound 20

##STR00138##

wherein A1, A3, A4, R7, X, Y and Z of Formula I-A are
as defined herein and LG is Br, Cl or --OH, with a compound having the
structure

##STR00139##

R2--B(OH)2 or R2--Br, wherein R2 is as defined
herein, to make a compound of Formula I-A.

[0790] In another embodiment of the invention, there is provided a method
of making a compound of Formula I-B, the method comprising the step of
reacting a compound 20

##STR00140##

wherein A4, R7, X, Y and Z of Formula I-B are as defined herein
and LG is Br, Cl or --OH, with a compound having the structure

##STR00141##

R2--B(OH)2 or R2--Br, wherein R2 is as defined
herein, to make a compound of Formula I-B.

[0791] In another embodiment of the invention, there is provided a method
of making a compound of Formula II, the method comprising the step of
reacting a compound 20

##STR00142##

wherein A1, A2, A3, A4, A5, A6, R2, X
and Y of Formula II are as defined herein, with a compound having the
structure

##STR00143##

or R7--B(OH)2, wherein R7 is as defined herein, to make a
compound of Formula II.

[0792] As can be appreciated by the skilled artisan, the above synthetic
schemes and representative examples are not intended to comprise a
comprehensive list of all means by which the compounds described and
claimed in this application may be synthesized. Further methods will be
evident to those of ordinary skill in the art. Additionally, the various
synthetic steps described above may be performed in an alternate sequence
or order to give the desired compounds.

[0793] For example, in these procedures, the steps may be preceded, or
followed, by additional protection/deprotection steps as necessary.
Particularly, if one or more functional groups, for example carboxy,
hydroxy, amino, or mercapto groups, are or need to be protected in
preparing the compounds of the invention, because they are not intended
to take part in a specific reaction or chemical transformation, various
known conventional protecting groups may be used. For example, protecting
groups typically utilized in the synthesis of natural and synthetic
compounds, including peptides, nucleic acids, derivatives thereof and
sugars, having multiple reactive centers, chiral centers and other sites
potentially susceptible to the reaction reagents and/or conditions, may
be used.

[0795] Salts, including pharmaceutically acceptable salts, of a compound
of the invention having a salt-forming group may be prepared in a
conventional manner or manner known to persons skilled in the art. For
example, acid addition salts of compounds of the invention may be
obtained by treatment with an acid or with a suitable anion exchange
reagent. A salt with two acid molecules (for example a dihalogenide) may
also be converted into a salt with one acid molecule per compound (for
example a monohalogenide); this may be done by heating to a melt, or for
example by heating as a solid under a high vacuum at elevated
temperature, for example from 50° C. to 170° C., one
molecule of the acid being expelled per molecule of the compound.

[0796] Acid salts can usually be converted to free-base compounds, e.g. by
treating the salt with suitable basic agents, for example with alkali
metal carbonates, alkali metal hydrogen carbonates, or alkali metal
hydroxides, typically potassium carbonate or sodium hydroxide. Exemplary
and suitable salts, and their preparation, are described herein in the
Definition section of the application.

[0797] All synthetic procedures described herein can be carried out under
known reaction conditions, advantageously under those described herein,
either in the absence or in the presence (usually) of solvents or
diluents. As appreciated by those of ordinary skill in the art, the
solvents should be inert with respect to, and should be able to dissolve,
the starting materials and other reagents used. Solvents should be able
to partially or wholly solubilize the reactants in the absence or
presence of catalysts, condensing agents or neutralizing agents, for
example ion exchangers, typically cation exchangers for example in the
H.sup.+ form. The ability of the solvent to allow and/or influence the
progress or rate of the reaction is generally dependant on the type and
properties of the solvent(s), the reaction conditions including
temperature, pressure, atmospheric conditions such as in an inert
atmosphere under argon or nitrogen, and concentration, and of the
reactants themselves.

[0798] Suitable solvents for conducting reactions to synthesize compounds
of the invention include, without limitation, water; esters, including
lower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphatic
ethers, e.g., Et2O and ethylene glycol dimethylether or cyclic
ethers, e.g., THF; liquid aromatic hydrocarbons, including benzene,
toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n-
and t-butanol; nitriles including CH3CN; halogenated hydrocarbons,
including CH2Cl2, CHCl3 and CCL4; acid amides
including DMF; sulfoxides, including DMSO; bases, including heterocyclic
nitrogen bases, e.g. pyridine; carboxylic acids, including lower
alkanecarboxylic acids, e.g., AcOH; inorganic acids including HCl, HBr,
HF, H2SO4 and the like; carboxylic acid anhydrides, including
lower alkane acid anhydrides, e.g., acetic anhydride; cyclic, linear, or
branched hydrocarbons, including cyclohexane, hexane, pentane, isopentane
and the like, and mixtures of these solvents, such as purely organic
solvent combinations, or water-containing solvent combinations e.g.,
aqueous solutions. These solvents and solvent mixtures may also be used
in "working-up" the reaction as well as in processing the reaction and/or
isolating the reaction product(s), such as in chromatography.

[0799] Purification methods are known in the art and include, for example,
crystallization, chromatography (liquid and gas phase, and the like),
extraction, distillation, trituration, reverse phase HPLC and the like.
Reactions conditions such as temperature, duration, pressure, and
atmosphere (inert gas, ambient) are known in the art and may be adjusted
as appropriate for the reaction.

[0800] The invention further encompasses "intermediate" compounds,
including structures produced from the synthetic procedures described,
whether isolated or generated in-situ and not isolated, prior to
obtaining the finally desired compound. Structures resulting from
carrying out steps from a transient starting material, structures
resulting from divergence from the described method(s) at any stage, and
structures forming starting materials under the reaction conditions are
all "intermediates" included in the invention. Further, structures
produced by using starting materials in the form of a reactive derivative
or salt, or produced by a compound obtainable by means of the process
according to the invention and structures resulting from processing the
compounds of the invention in situ are also within the scope of the
invention.

[0801] The invention also provides new starting materials and/or
intermediates, as well as processes for the preparation thereof. In
select embodiments, such starting materials are used and reaction
conditions so selected as to obtain the desired compound(s). Starting
materials of the invention, are either known, commercially available, or
can be synthesized in analogy to or according to methods that are known
in the art. Many starting materials may be prepared according to known
processes and, in particular, can be prepared using processes described
in the examples. In synthesizing starting materials, functional groups
may be protected with suitable protecting groups when necessary.
Protecting groups, their introduction and removal are described above.

[0802] Compounds of the present invention can possess, in general, one or
more asymmetric carbon atoms and are thus capable of existing in the form
of optical isomers as well as in the form of racemic or non-racemic
mixtures thereof. While shown without respect to stereochemistry in
Formulas I-II, the present invention includes such optical isomers and
diastereomers, as well as the racemic and resolved, enantiomerically pure
R and S stereoisomers, as well as other mixtures of R and S stereoisomers
and pharmaceutically acceptable salts thereof.

[0803] The optical isomers can be obtained by resolution of the racemic
mixtures according to conventional processes, e.g., by formation of
diastereoisomeric salts, by treatment with an optically active acid or
base. Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then
separation of the mixture of diastereoisomers by crystallization followed
by liberation of the optically active bases from these salts. A different
process for separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation of the
enantiomers. Still another available method involves synthesis of
covalent diastereoisomeric molecules by reacting compounds of the
invention with an optically pure acid in an activated form or an
optically pure isocyanate. The synthesized diastereoisomers can be
separated by conventional means such as chromatography, distillation,
crystallization or sublimation, and then hydrolyzed to deliver the
enantiomerically pure compound. The optically active compounds of the
invention can likewise be obtained by using optically active starting
materials. These isomers may be in the form of a free acid, a free base,
an ester or a salt. All such isomeric forms of such compounds are
expressly included in the present invention.

[0804] The compounds of the invention may also be represented in multiple
tautomeric forms. Tautomers often exist in equilibrium with each other,
and interconvert under environmental and physiological conditions. The
compounds of the invention may also occur in cis- or trans- or E- or
Z-double bond isomeric forms. The invention expressly includes all
tautomeric forms of the compounds described herein.

[0805] All crystal forms of the compounds described herein are expressly
included in the present invention.

[0806] The present invention also includes isotopically-labeled compounds,
which are identical to those recited herein, but for the fact that one or
more atoms are replaced by an atom having an atomic mass or mass number
different from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine and chlorine, such as 2H (deuterium), 3H
(tritium), 13C, 14C, 15N, 16O, 17O, 31P,
32P, 35S, 18F, and 36Cl.

[0807] Compounds of the present invention that contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope of
this invention. Certain isotopically-labeled compounds of the present
invention, for example those into which radioactive isotopes such as
3H and 14C are incorporated, are useful in drug and/or
substrate tissue distribution assays. Deuterated (2H), Tritiated
(3H) and carbon-14, i.e., 14C, isotopes are particularly
preferred for their ease of preparation and detection. Further,
substitution with heavier isotopes such as deuterium, i.e., 2H, can
afford certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances.
Isotopically labeled compounds of this invention can generally be
prepared by substituting a readily available isotopically labeled reagent
for a non-isotopically labeled reagent.

Biological Evaluation

[0808] The compounds of the invention may be modified by appending
appropriate functionalities to enhance selective biological properties.
The pharmacokinetic and pharmacodynamic properties of a compound relate,
directly and indirectly, to the ability of the compound to be effective
for its intended use.

[0809] Although the pharmacological properties of the compounds of the
invention (Formulas I-II and sub-Formulas thereof) vary with structural
change, in general, activity possessed by compounds of Formulas I-II may
be demonstrated both in vitro as well as in vivo. The following
exemplified pharmacological assays have been carried out with the
compounds according to the invention, to assess and characterize the
compound's ability to modulate BACE activity and to regulate the cleavage
of amyloid beta precursor protein, thereby reducing or inhibiting the
production of amyloid beta.

[0810] The assay buffer used in this screen is 0.05 M acetate, pH 4.2, 10%
DMSO final, 100 uM genapol (which is a nonionic detergent, below its
Critical Micelle Concentration). The beta secretase enzyme (0.2 nM) is
pre-incubated for one hour with inhibitors, typically in about 1 μL of
DMSO according to a serial dilution, are added thereto. This assay is
effectively started by the addition of FRET substrate (50 nM) and the
combination is incubated for one hour. The FRET assay is terminated with
by addition of Tris buffer, which raises the pH to neutrality, and the
fluorescence is determined. The FRET substrate is a peptide with
commercially available fluorophore and quencher, on opposite sides of the
BACE cleavage site. Proteolytic cleavage of the FRET substrate releases
quenching of fluorescence (excitation 488 nm and emission 425 nm).

[0811] Where available, the in-vitro BACE FRET enzyme data for each of the
Examples is provided in Table I.

[0813] Cells stably expressing Amyloid Precursor Protein (APP) were plated
at a density of 40K cells/well in 96 well plates (Costar). The cells were
cultivated for 24 hours at 37° C. and 5% CO2 in DMEM
supplemented with 10% FBS. The test compounds were then added to cells in
10-point dose response concentrations with the starting concentration
being either 100 μM or 10 μM. The compounds were diluted from stock
solutions in DMSO and the final DMSO concentration of the test compounds
on cells was 0.1%. After 24 h of incubation with the test compounds the
supernatant conditioned media was collected and the Aβ 40 levels
were determined using a sandwich ELISA. The IC50 of the compound was
calculated from the percent of control or percent inhibition of Aβ
40 as a function of the concentration of the test compound.

[0814] The sandwich ELISA to detect Aβ 40 was performed in 96 well
microtiter plates, which were pre-treated with goat anti-rabbit IgG
(Pierce). The capture and detecting antibody pair that were used to
detect Aβ 40 from cell supernatants were affinity purified pAb40
(Biosource) and biotinylated 6E10 (Signet Labs Inc.), respectively. The
optimal concentration for the pAb40 antibody was 3 μg/ml in
Superblock/TBS (Pierce) that was supplemented with 0.05% Tween 20
(Sigma). Optimal concentration for the detection antibody
6E10-biotinylated was 0.5 μg/ml in Superblock/TBS (Pierce) that had
been supplemented with 2% normal goat serum and 2% normal mouse serum.

[0815] Cellular supernatants were incubated with the capture antibody for
3 h at 4° C., followed by 3 wash steps in TBS-tween (0.05%). The
detecting antibody incubation was for 2 h at 4° C., again followed
by the wash steps as described previously. The final readout of the ELISA
is Time-Resolved Fluorescence (counts per minute) using Delfia reagents
Streptavidin-Europium and Enhancement solutions (Perkin Elmer) and the
Victor 2 multilabel counter (Perkin Elmer).

[0816] Where available, the in-vitro BACE cell based data for each of the
Examples is provided in Table I.

In Vivo Inhibition of Beta-Secretase

[0817] Several animal models, including mouse, rat, dog, and monkey, may
be used to screen for inhibition of beta-secretase activity in vivo
following administration of a test compound sample. Animals used in this
invention can be wild type, transgenic, or gene knockout animals. For
example, the Tg2576 mouse model, prepared and conducted as described in
Hsiao et al., 1996, Science 274, 99-102, and other non-transgenic or gene
knockout animals are useful to analyze in vivo inhibition of Amyloid beta
peptide (Abeta) production in the presence of inhibitory test compounds.
Generally, 2 to 18 month old Tg2576 mice, gene knockout mice or
non-transgenic animals are administered test compounds formulated in
vehicles, such as cyclodextran, phosphate buffers, hydroxypropyl
methylcellulose or other suitable vehicles. One to twenty-four hours
following the administration of compound, animals are sacrificed, and
brains as well as cerebrospinal fluid (CSF) and plasma are removed for
analysis of A-beta levels and drug or test compound concentrations (Dovey
et al., 2001, Journal of Neurochemistry, 76, 173-181) Beginning at time
0, animals are administered by oral gavage, or other means of delivery
such as intravenous injection, an inhibitory test compound of up to 100
mg/kg in a standard, conventional formulation, such as 2% hydroxypropyl
methylcellulose, 1% Tween80. A separate group of animals receive 2%
hydroxypropyl methylcellulose, 1% Tween80 alone, containing no test
compound, and serve as a vehicle-control group. At the end of the test
period, animals are sacrificed and brain tissues, plasma or cerebrospinal
fluid are collected. Brains are either homogenized in 10 volumes (w/v) of
0.2% diethylamine (DEA) in 50 mM NaCl (Best et al., 2005, Journal of
Pharmacology and Experimental Therapeutics, 313, 902-908), or in 10
volumes of 0.5% TritonX-100 in Tris-buffered saline (pH at about 7.6).
Homogenates are centrifuged at 355,000 g, 4° C. for 30 minutes.
CSF or brain supernatants are then analyzed for the presence of A-beta
peptide by specific sandwich ELISA assays based on ECL
(Electrochemiluminescence) technology. For example, rat Abeta40 is
measured using biotinylated-4G8 (Signet) as a capture antibody and Fab40
(an in-house antibody specific to the C-terminal of Abeta40) as a
detection antibody. For example, 4 hours after administration of 30 mg/kg
oral dose of the test compound in 2% hydroxypropyl methylcellulose, 1%
Tween80 (pH2.2) to 200 g male Sprague Dawley rats, amyloid beta peptide
levels are measured for reduction by X % and Y % in cerebrospinal fluid
and brain, respectively, when compared to the levels measured in the
vehicle-treated rats.

[0819] The compounds of the invention may be shown to reduce the formation
and/or deposition of amyloid beta peptide in the cerebrospinal fluid
(CSF) as well as in the brain of a mouse or rat at either 3 mpk, 10 mpk
or 30 mpk (mpk=mg compound per kg weight of the animal) dosing
concentrations after 4 hrs. The following examples exhibited the
following percent Abeta 40 reductions at 10 mpk (unless otherwise noted)
in the CSF and brain of the rat, respectively.

[0820] The compounds of the invention have been shown to modulate, and
specifically inhibit the activity of beta-secretase (Memapsin 2) enzyme,
thereby reducing the A-beta peptide fragments believed to be responsible
for Alzheimer's Disease (AD). Bapineuzamab, a monoclonal amino-terminus
specific anti-amyloid antibody is presently in Phase III clinical trials
for the treatment of AD. Alzheimer's Research & Therapy, 1:2, 2009.
Bapineuzumab targets beta amyloid protein involved in AD. It is the most
advanced monoclonal antibody in clinical development to stop the disease
progression and degradation of cognitive function. The drug has fast
track regulatory status with the USFDA (Medpedia, 2011). Hence, it must
clearly show a beneficial and lasting effect through validated biomarker
of underlying AD disease mechanism. Clinical trials in AD now measure CSF
Aβ levels, brain amyloid load, CSF tau, brain volume by MRI and FDG
PET scan. Each of the known genetic causes of AD is linked to A-beta.

[0821] Other conditions including dementia, Down's Syndrome to APP
over-production, are all believed to be linked to the deposition of
A-beta on the brain. With methods for identifying brain amyloid
deposition, positron emission scanning (PET) and CSF measurements of
Ab42, identification of AD suffering individuals needing treatment is
becoming more easy. It is firmly believed that by reducing the formation
of A-beta, one can begin to pre-treat AD. Vassar et al, Journal of
Neuroscience, 29 (41):12787-12794, 2009. One published pathway for
treatment of AD is inhibition of beta-secretase. Tirrell, Bloomberg News,
The Boston Globe, Jan. 7, 2010; Curr. Alzheimer's Res. 2008, April 5
(2):121-131; Expert Opin. Drug Discov. (200( ) 4(4):319-416.

[0822] Accordingly, compounds of the invention, and pharmaceutical
compositions comprising said compounds, are useful for, but not limited
to, the prevention or treatment of beta-secretase related diseases,
including Alzheimer's disease, the leading cause of dementia.
Particularly, the compounds of the invention are useful to treat various
stages of AD, including without limitation mild to moderate AD and
prodromal patients pre-disposed to developing AD. The compounds of the
invention have the ability to modulate the activity of beta secretase
enzyme, thereby regulating the production of amyloid beta (Abeta peptide)
and slowing or reducing the formation and deposition of Abeta peptide in
both the cerebral spinal fluid as well as in the brain, resulting in a
decrease of amyloid plaque on the brain. In one embodiment of the
invention, there is provided a method of treating a disorder related to a
beta-secretase enzyme in a subject, the method comprising administering
to the subject an effective dosage amount of a compound of Formulas I,
I-A,I-A-1 through I-A-7, I-B, II, II-A or II-B. In another embodiment,
there is provided a method of reducing production of amyloid beta, and of
slowing plaque formation on the brain. In another embodiment, there is
provided a method for the treatment, prevention or amelioration of a
disease or disorder characterized by the elevated beta-amyloid deposits
or beta-amyloid levels in a subject, the method comprising administering
to the subject a therapeutically effective amount of a compound according
to any of Formulas I-II, and sub-Formulas thereof. In yet another
embodiment, the invention provides a method of treating Alzheimer's
disease, cognitive impairment including mild, moderate and/or severe,
Down's Syndrome, cognitive decline, senile dementia, cerebral amyloid
angiopathy or a neurodegenerative disorder.

[0823] Accordingly, the compounds of the invention would be useful in
therapy as CNS agents in treating neurological disorders and related
conditions.

[0824] In one embodiment, the compounds of the invention are provided for
the manufacture of a medicament, or a pharmaceutical composition, for the
therapeutic and/or prophylactic treatment of diseases and disorders
characterized by elevated levels of β-amyloid and/or β-amyloid
oligomers and/or b-amyloid plaques and further deposits, including
Alzheimer's Disease. In another embodiment, the invention provides
compounds, in effective dosage amounts, for the therapeutic and/or
prophylactic treatment of AD. Thus, the compounds of the invention may be
used to treat prodromol patients, i.e., subjects exhibiting the
biomarkers and/or hallmarks of developing AD.

[0825] Besides being useful for human treatment, these compounds are
useful for veterinary treatment of companion animals, exotic animals and
farm animals, including mammals, rodents, and the like. For example,
animals including horses, dogs, and cats may be treated with compounds
provided by the invention.

Formulations and Method of Use

[0826] Treatment of diseases and disorders herein is intended to also
include therapeutic administration of a compound of the invention, or a
pharmaceutical salt thereof, or a pharmaceutical composition of either to
a subject (i.e., an animal, preferably a mammal, most preferably a human)
which may be in need of preventative treatment, such as, for example, for
pain, inflammation and the like. Treatment also encompasses prophylactic
administration of a compound of the invention, or a pharmaceutical salt
thereof, or a pharmaceutical composition of either to a subject (i.e., an
animal, preferably a mammal, most preferably a human). Generally, the
subject is initially diagnosed by a licensed physician and/or authorized
medical practitioner, and a regimen for prophylactic and/or therapeutic
treatment via administration of the compound(s) or compositions of the
invention is suggested, recommended or prescribed.

[0827] The amount of compound(s) which is/are administered and the dosage
regimen for treating neurological disorders and beta-secretase mediated
diseases with the compounds and/or compositions of this invention depends
on a variety of factors, including the age, weight, sex and medical
condition of the subject, the type of disease, the severity of the
disease, the route and frequency of administration, and the particular
compound employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about 0.01
to 500 mg/kg, advantageously between about 0.01 and about 50 mg/kg, more
advantageously about 0.01 and about 30 mg/kg, and even more
advantageously between about 0.1 and about 10 mg/kg body weight may be
appropriate, and should be useful for all methods of use disclosed
herein. The daily dose can be administered in one to four doses per day.

[0828] While it may be possible to administer a compound of the invention
alone, in the methods described, the compound administered normally will
be present as an active ingredient in a pharmaceutical composition. Thus,
in another embodiment of the invention, there is provided a
pharmaceutical composition comprising a compound of this invention in
combination with a pharmaceutically acceptable excipient, which includes
diluents, carriers, adjuvants and the like (collectively referred to
herein as "excipient" materials) as described herein, and, if desired,
other active ingredients. A pharmaceutical composition of the invention
may comprise an "effective amount" of a compound of the invention or an
"effective dosage amount" of a compound of the invention. An "effective
dosage amount" of a compound of the invention includes an amount less
than, equal to or greater than an effective amount of the compound. For
example, a pharmaceutical composition in which two or more unit dosages,
such as in tablets, capsules and the like, are required to administer an
effective amount of the compound, or alternatively, a multi-dose
pharmaceutical composition, such as powders, liquids and the like, in
which an effective amount of the compound is administered by
administering a portion of the composition.

[0829] The compound(s) of the present invention may be administered by any
suitable route, preferably in the form of a pharmaceutical composition
adapted to such a route, and in a dose effective for the treatment
intended. The compounds and compositions of the present invention may,
for example, be administered orally, mucosally, topically, rectally,
pulmonarily such as by inhalation spray, or parentally including
intravascularly, intravenously, intraperitoneally, subcutaneously,
intramuscularly intrasternally and infusion techniques, in dosage unit
formulations containing conventional pharmaceutically acceptable
carriers, adjuvants, and vehicles.

[0830] For oral administration, the pharmaceutical composition may be in
the form of, for example, a tablet, capsule, suspension or liquid. The
pharmaceutical composition is preferably made in the form of a dosage
unit containing a particular amount of the active ingredient. Examples of
such dosage units are tablets or capsules. For example, these may contain
an amount of active ingredient from about 1 to 2000 mg, advantageously
from about 1 to 500 mg, and typically from about 5 to 150 mg. A suitable
daily dose for a human or other mammal may vary widely depending on the
condition of the patient and other factors, but, once again, can be
determined using routine methods and practices.

[0831] For therapeutic purposes, the active compounds of this invention
are ordinarily combined with one or more adjuvants or other "excipients"
appropriate to the indicated route of administration. If orally
administered on a per dose basis, the compounds may be admixed with
lactose, sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium
oxide, sodium and calcium salts of phosphoric and sulfuric acids,
gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or
polyvinyl alcohol, to form the final formulation. For example, the active
compound(s) and excipient(s) may be tableted or encapsulated by known and
accepted methods for convenient administration. Examples of suitable
formulations include, without limitation, pills, tablets, soft and
hard-shell gel capsules, troches, orally-dissolvable forms and delayed or
controlled-release formulations thereof. Particularly, capsule or tablet
formulations may contain one or more controlled-release agents, such as
hydroxypropylmethyl cellulose, as a dispersion with the active
compound(s).

[0832] Formulations for parenteral administration may be in the form of
aqueous or non-aqueous isotonic sterile injection solutions or
suspensions. These solutions and suspensions may be prepared from sterile
powders or granules using one or more of the carriers or diluents
mentioned for use in the formulations for oral administration or by using
other suitable dispersing or wetting agents and suspending agents. The
compounds may be dissolved in water, polyethylene glycol, propylene
glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl
alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other
adjuvants and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered by
injection as a composition with suitable carriers including saline,
dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent
solubilization (ie. propylene glycol) or micellar solubilization (ie.
Tween 80).

[0833] The sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid find
use in the preparation of injectables.

[0834] The active ingredient may also be administered by injection as a
composition with suitable carriers including saline, dextrose, or water.
The daily parenteral dosage regimen will be from about 0.1 to about 30
mg/kg of total body weight, and preferably from about 0.1 to about 10
mg/kg.

[0835] For pulmonary administration, the pharmaceutical composition may be
administered in the form of an aerosol or with an inhaler including dry
powder aerosol.

[0836] The pharmaceutical compositions may be subjected to conventional
pharmaceutical operations such as sterilization and/or may contain
conventional adjuvants, such as preservatives, stabilizers, wetting
agents, emulsifiers, buffers etc. Tablets and pills can additionally be
prepared with enteric coatings. Such compositions may also comprise
adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
Accordingly, in yet another embodiment of the present invention, there is
provided a method of manufacturing a medicament, the method comprising
combining an amount of a compound according to Formulas I-II with a
pharmaceutically acceptable carrier to manufacture the medicament.

[0837] In yet another embodiment, the invention provides a method of
manufacturing a medicament for the treatment of Alzheimer's disease, the
method comprising combining an amount of a compound according to Formulas
I-II with a pharmaceutically acceptable carrier to manufacture the
medicament.

Combinations

[0838] While the compounds of the invention can be dosed or administered
as the sole active pharmaceutical agent, they can also be used in
combination with one or more compounds of the invention or in conjunction
with other agents. When administered as a combination, the therapeutic
agents can be formulated as separate compositions that are administered
simultaneously or sequentially at different times, or the therapeutic
agents can be given as a single composition.

[0839] The phrase "co-therapy" (or "combination-therapy"), in defining use
of a compound of the present invention and another pharmaceutical agent,
is intended to embrace administration of each agent in a sequential
manner in a regimen that will provide beneficial effects of the drug
combination, and is intended as well to embrace co-administration of
these agents in a substantially simultaneous manner, such as in a single
capsule having a fixed ratio of these active agents or in multiple,
separate capsules for each agent.

[0840] Specifically, the compounds of the present invention may be
administered in conjunction with additional therapies known to those
skilled in the art in the prevention or treatment of beta-secretase,
gamma-secretase and/or other reagents known in influence the formation
and/or deposition of amyloid beta, otherwise responsible for the
formation of plaque on the brain. Thus, the compounds may be
co-administered simultaneously or sequentially along with the other
therapeutic agent.

[0841] If formulated as a fixed dose, such combination products employ the
compounds of this invention within the accepted dosage ranges. Compounds
of Formulas I and II may also be administered sequentially with known CNS
treating agents when a combination formulation is inappropriate. The
invention is not limited in the sequence of administration; compounds of
the invention may be administered either prior to, simultaneous with or
after administration of the known and used CNS agent.

[0842] The foregoing description is merely illustrative of the invention
and is not intended to limit the invention to the disclosed compounds,
compositions and methods. Variations and changes, which are obvious to
one skilled in the art, are intended to be within the scope and nature of
the invention, as defined in the appended claims. From the foregoing
description, one skilled in the art can easily ascertain the essential
characteristics of this invention, and without departing from the spirit
and scope thereof, can make various changes and modifications of the
invention to adapt it to various usages and conditions. All patents and
other publications recited herein are hereby incorporated by reference in
their entireties.